Thrombosis

Researchers have developed a quick and easy scoring system to predict which hospitalized COVID-19 patients are more at risk for stroke.

“The system is simple. You can calculate the points in 5 seconds and then predict the chances the patient will have a stroke,” Alexander E. Merkler, MD, assistant professor of neurology at Weill Cornell Medical College/NewYork-Presbyterian Hospital, and lead author of a study of the system, told this news organization.

The new system will allow clinicians to stratify patients and lead to closer monitoring of those at highest risk for stroke, said Dr. Merkler.

The study was presented during the International Stroke Conference, presented by the American Stroke Association, a division of the American Heart Association.

Some, but not all, studies suggest COVID-19 increases the risk of stroke and worsens stroke outcomes, and the association isn’t clear, investigators note.

Researchers used the American Heart Association Get With the Guidelines COVID-19 cardiovascular disease registry for this analysis. They evaluated 21,420 adult patients (mean age 61 years, 54% men), who were hospitalized with COVID-19 at 122 centers from March 2020 to March 2021.

Investigators tapped into the vast amounts of data in this registry on different variables, including demographics, comorbidities, and lab values.

The outcome was a cerebrovascular event, defined as any ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or cerebral vein thrombosis. Of the total hospitalized COVID-19 population, 312 (1.5%) had a cerebrovascular event.

Researchers first used standard statistical models to determine which risk factors are most associated with the development of stroke. They identified six such factors:

• history of stroke
• no fever at the time of hospital admission
• no history of pulmonary disease
• high white blood cell count
• history of hypertension
• high systolic blood pressure at the time of hospital admission

That the list of risk factors included absence of fever and no history of pulmonary disease was somewhat surprising, said Dr. Merkler, but there may be possible explanations, he added.

A high fever is an inflammatory response, and perhaps patients who aren’t responding appropriately “could be sicker in general and have a poor immune system, and thereby be at increased risk for stroke,” said Dr. Merkler.

In the case of pulmonary disease, patients without a history who are admitted for COVID “may have an extremely high burden of COVID, or are extremely sick, and that’s why they’re at higher risk for stroke.”

The scoring system assigns points for each variable, with more points conferring a higher risk of stroke. For example, someone who has 0-1 points has 0.2% risk of having a stroke, and someone with 4-6 points has 2% to 3% risk, said Dr. Merkler.

“So, we’re talking about a 10- to 15-fold increased risk of having a stroke with 4 to 6 versus 0 to 1 variables.”

The accuracy of the risk stratification score (C-statistic of 0.66; 95% confidence interval, 0.60-0.72) is “fairly good or modestly good,” said Dr. Merkler.

A patient with a score of 5 or 6 may need more vigilant monitoring to make sure symptoms are caught early and therapies such as thrombolytics and thrombectomy are readily available, he added.

Researchers also used a sophisticated machine-learning approach where a computer takes all the variables and identifies the best algorithm to predict stroke.

“The machine-learning algorithm was basically just as good as our standard model; it was almost identical,” said Dr. Merkler.

Outside of COVID, other scoring systems are used to predict stroke. For example, the ABCD2 score uses various factors to predict risk of recurrent stroke.

Philip B. Gorelick, MD, adjunct professor, Northwestern University Feinberg School of Medicine, Chicago, said the results are promising, as they may lead to identifying modifiable factors to prevent stroke.

Dr. Gorelick noted that the authors identified risk factors to predict risk of stroke “after an extensive analysis of baseline factors that included an internal validation process.”

The finding that no fever and no history of pulmonary disease were included in those risk factors was “unexpected,” said Dr. Gorelick, who is also medical director of the Hauenstein Neuroscience Center in Grand Rapids, Michigan. “This may reflect the baseline timing of data collection.”

He added further validation of the results in other data sets “will be useful to determine the consistency of the predictive model and its potential value in general practice.”

Louise D. McCullough, MD, PhD, professor and chair of neurology, McGovern Medical School, The University of Texas Health Science Center, Houston, said the association between stroke risk and COVID exposure “has been very unclear.”

“Some people find a very strong association between stroke and COVID, some do not,” said Dr. McCullough, who served as the chair of the ISC 2022 meeting.

This new study looking at a risk stratification model for COVID patients was “very nicely done,” she added.

“They used the American Heart Association Get With The Guidelines COVID registry, which was an amazing feat that was done very quickly by the AHA to establish COVID reporting in the Get With The Guidelines data, allowing us to really look at other factors related to stroke that are in this unique database.”

The study received funding support from the American Stroke Association. Dr. Merkler has received funding from the American Heart Association and the Leon Levy Foundation. Dr. Gorelick was not involved in the study and has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Researchers have developed a quick and easy scoring system to predict which hospitalized COVID-19 patients are more at risk for stroke.

“The system is simple. You can calculate the points in 5 seconds and then predict the chances the patient will have a stroke,” Alexander E. Merkler, MD, assistant professor of neurology at Weill Cornell Medical College/NewYork-Presbyterian Hospital, and lead author of a study of the system, told this news organization.

The new system will allow clinicians to stratify patients and lead to closer monitoring of those at highest risk for stroke, said Dr. Merkler.

The study was presented during the International Stroke Conference, presented by the American Stroke Association, a division of the American Heart Association.

Some, but not all, studies suggest COVID-19 increases the risk of stroke and worsens stroke outcomes, and the association isn’t clear, investigators note.

Researchers used the American Heart Association Get With the Guidelines COVID-19 cardiovascular disease registry for this analysis. They evaluated 21,420 adult patients (mean age 61 years, 54% men), who were hospitalized with COVID-19 at 122 centers from March 2020 to March 2021.

Investigators tapped into the vast amounts of data in this registry on different variables, including demographics, comorbidities, and lab values.

The outcome was a cerebrovascular event, defined as any ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or cerebral vein thrombosis. Of the total hospitalized COVID-19 population, 312 (1.5%) had a cerebrovascular event.

Researchers first used standard statistical models to determine which risk factors are most associated with the development of stroke. They identified six such factors:

• history of stroke
• no fever at the time of hospital admission
• no history of pulmonary disease
• high white blood cell count
• history of hypertension
• high systolic blood pressure at the time of hospital admission

That the list of risk factors included absence of fever and no history of pulmonary disease was somewhat surprising, said Dr. Merkler, but there may be possible explanations, he added.

A high fever is an inflammatory response, and perhaps patients who aren’t responding appropriately “could be sicker in general and have a poor immune system, and thereby be at increased risk for stroke,” said Dr. Merkler.

In the case of pulmonary disease, patients without a history who are admitted for COVID “may have an extremely high burden of COVID, or are extremely sick, and that’s why they’re at higher risk for stroke.”

The scoring system assigns points for each variable, with more points conferring a higher risk of stroke. For example, someone who has 0-1 points has 0.2% risk of having a stroke, and someone with 4-6 points has 2% to 3% risk, said Dr. Merkler.

“So, we’re talking about a 10- to 15-fold increased risk of having a stroke with 4 to 6 versus 0 to 1 variables.”

The accuracy of the risk stratification score (C-statistic of 0.66; 95% confidence interval, 0.60-0.72) is “fairly good or modestly good,” said Dr. Merkler.

A patient with a score of 5 or 6 may need more vigilant monitoring to make sure symptoms are caught early and therapies such as thrombolytics and thrombectomy are readily available, he added.

Researchers also used a sophisticated machine-learning approach where a computer takes all the variables and identifies the best algorithm to predict stroke.

“The machine-learning algorithm was basically just as good as our standard model; it was almost identical,” said Dr. Merkler.

Outside of COVID, other scoring systems are used to predict stroke. For example, the ABCD2 score uses various factors to predict risk of recurrent stroke.

Philip B. Gorelick, MD, adjunct professor, Northwestern University Feinberg School of Medicine, Chicago, said the results are promising, as they may lead to identifying modifiable factors to prevent stroke.

Dr. Gorelick noted that the authors identified risk factors to predict risk of stroke “after an extensive analysis of baseline factors that included an internal validation process.”

The finding that no fever and no history of pulmonary disease were included in those risk factors was “unexpected,” said Dr. Gorelick, who is also medical director of the Hauenstein Neuroscience Center in Grand Rapids, Michigan. “This may reflect the baseline timing of data collection.”

He added further validation of the results in other data sets “will be useful to determine the consistency of the predictive model and its potential value in general practice.”

Louise D. McCullough, MD, PhD, professor and chair of neurology, McGovern Medical School, The University of Texas Health Science Center, Houston, said the association between stroke risk and COVID exposure “has been very unclear.”

“Some people find a very strong association between stroke and COVID, some do not,” said Dr. McCullough, who served as the chair of the ISC 2022 meeting.

This new study looking at a risk stratification model for COVID patients was “very nicely done,” she added.

“They used the American Heart Association Get With The Guidelines COVID registry, which was an amazing feat that was done very quickly by the AHA to establish COVID reporting in the Get With The Guidelines data, allowing us to really look at other factors related to stroke that are in this unique database.”

The study received funding support from the American Stroke Association. Dr. Merkler has received funding from the American Heart Association and the Leon Levy Foundation. Dr. Gorelick was not involved in the study and has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Researchers have developed a quick and easy scoring system to predict which hospitalized COVID-19 patients are more at risk for stroke.

“The system is simple. You can calculate the points in 5 seconds and then predict the chances the patient will have a stroke,” Alexander E. Merkler, MD, assistant professor of neurology at Weill Cornell Medical College/NewYork-Presbyterian Hospital, and lead author of a study of the system, told this news organization.

The new system will allow clinicians to stratify patients and lead to closer monitoring of those at highest risk for stroke, said Dr. Merkler.

The study was presented during the International Stroke Conference, presented by the American Stroke Association, a division of the American Heart Association.

Some, but not all, studies suggest COVID-19 increases the risk of stroke and worsens stroke outcomes, and the association isn’t clear, investigators note.

Researchers used the American Heart Association Get With the Guidelines COVID-19 cardiovascular disease registry for this analysis. They evaluated 21,420 adult patients (mean age 61 years, 54% men), who were hospitalized with COVID-19 at 122 centers from March 2020 to March 2021.

Investigators tapped into the vast amounts of data in this registry on different variables, including demographics, comorbidities, and lab values.

The outcome was a cerebrovascular event, defined as any ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or cerebral vein thrombosis. Of the total hospitalized COVID-19 population, 312 (1.5%) had a cerebrovascular event.

Researchers first used standard statistical models to determine which risk factors are most associated with the development of stroke. They identified six such factors:

• history of stroke
• no fever at the time of hospital admission
• no history of pulmonary disease
• high white blood cell count
• history of hypertension
• high systolic blood pressure at the time of hospital admission

That the list of risk factors included absence of fever and no history of pulmonary disease was somewhat surprising, said Dr. Merkler, but there may be possible explanations, he added.

A high fever is an inflammatory response, and perhaps patients who aren’t responding appropriately “could be sicker in general and have a poor immune system, and thereby be at increased risk for stroke,” said Dr. Merkler.

In the case of pulmonary disease, patients without a history who are admitted for COVID “may have an extremely high burden of COVID, or are extremely sick, and that’s why they’re at higher risk for stroke.”

The scoring system assigns points for each variable, with more points conferring a higher risk of stroke. For example, someone who has 0-1 points has 0.2% risk of having a stroke, and someone with 4-6 points has 2% to 3% risk, said Dr. Merkler.

“So, we’re talking about a 10- to 15-fold increased risk of having a stroke with 4 to 6 versus 0 to 1 variables.”

The accuracy of the risk stratification score (C-statistic of 0.66; 95% confidence interval, 0.60-0.72) is “fairly good or modestly good,” said Dr. Merkler.

A patient with a score of 5 or 6 may need more vigilant monitoring to make sure symptoms are caught early and therapies such as thrombolytics and thrombectomy are readily available, he added.

Researchers also used a sophisticated machine-learning approach where a computer takes all the variables and identifies the best algorithm to predict stroke.

“The machine-learning algorithm was basically just as good as our standard model; it was almost identical,” said Dr. Merkler.

Outside of COVID, other scoring systems are used to predict stroke. For example, the ABCD2 score uses various factors to predict risk of recurrent stroke.

Philip B. Gorelick, MD, adjunct professor, Northwestern University Feinberg School of Medicine, Chicago, said the results are promising, as they may lead to identifying modifiable factors to prevent stroke.

Dr. Gorelick noted that the authors identified risk factors to predict risk of stroke “after an extensive analysis of baseline factors that included an internal validation process.”

The finding that no fever and no history of pulmonary disease were included in those risk factors was “unexpected,” said Dr. Gorelick, who is also medical director of the Hauenstein Neuroscience Center in Grand Rapids, Michigan. “This may reflect the baseline timing of data collection.”

He added further validation of the results in other data sets “will be useful to determine the consistency of the predictive model and its potential value in general practice.”

Louise D. McCullough, MD, PhD, professor and chair of neurology, McGovern Medical School, The University of Texas Health Science Center, Houston, said the association between stroke risk and COVID exposure “has been very unclear.”

“Some people find a very strong association between stroke and COVID, some do not,” said Dr. McCullough, who served as the chair of the ISC 2022 meeting.

This new study looking at a risk stratification model for COVID patients was “very nicely done,” she added.

“They used the American Heart Association Get With The Guidelines COVID registry, which was an amazing feat that was done very quickly by the AHA to establish COVID reporting in the Get With The Guidelines data, allowing us to really look at other factors related to stroke that are in this unique database.”

The study received funding support from the American Stroke Association. Dr. Merkler has received funding from the American Heart Association and the Leon Levy Foundation. Dr. Gorelick was not involved in the study and has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Topline results from the phase 1 APOLLO study of SLN360, a short interfering ribonucleic acid (siRNA) targeting lipoprotein(a), showed it significantly reduced Lp(a) in a dose-dependent manner from 46% to up to 98%.

Reductions of up to 81% were maintained out to 150 days, according to a release from the developer of the drug, Silence Therapeutics.

High Lp(a) affects about one in five people worldwide and is a genetic risk factor for cardiovascular disease. There are no approved medications that selectively lower Lp(a), and levels cannot be significantly modified through lifestyle changes or any approved medications.

SLN360 is a siRNA that is designed to lower Lp(a) production by using the body’s natural process of RNA interference to target and silence messenger RNA transcribed from the LPA gene in liver cells.

The first-in-human APOLLO trial evaluated 32 patients with serum Lp(a) concentrations of at least 150 nmol/L and no cardiovascular disease who received a single subcutaneous dose of SLN360 (30 mg, 100 mg, less than or equal to 300 mg, or less than or equal to 600 mg) or placebo and were followed for up to 150 days.

No clinically important safety concerns were identified, although low-grade adverse events at the injection site occurred, most prominently at the highest dose, according to the company.

Study follow-up has been extended to 1 year. Patient enrollment continues in the multiple-ascending dose portion of the phase 1 study in patients with high Lp(a) and a confirmed history of stable atherosclerotic cardiovascular disease, the company statement notes.

Detailed results from APOLLO will be presented in a late-breaking clinical trials session at the American College of Cardiology Annual Scientific Session on April 3 by principal investigator Steven E. Nissen, MD, Cleveland Clinic.

A version of this article first appeared on Medscape.com.

Topline results from the phase 1 APOLLO study of SLN360, a short interfering ribonucleic acid (siRNA) targeting lipoprotein(a), showed it significantly reduced Lp(a) in a dose-dependent manner from 46% to up to 98%.

Reductions of up to 81% were maintained out to 150 days, according to a release from the developer of the drug, Silence Therapeutics.

High Lp(a) affects about one in five people worldwide and is a genetic risk factor for cardiovascular disease. There are no approved medications that selectively lower Lp(a), and levels cannot be significantly modified through lifestyle changes or any approved medications.

SLN360 is a siRNA that is designed to lower Lp(a) production by using the body’s natural process of RNA interference to target and silence messenger RNA transcribed from the LPA gene in liver cells.

The first-in-human APOLLO trial evaluated 32 patients with serum Lp(a) concentrations of at least 150 nmol/L and no cardiovascular disease who received a single subcutaneous dose of SLN360 (30 mg, 100 mg, less than or equal to 300 mg, or less than or equal to 600 mg) or placebo and were followed for up to 150 days.

No clinically important safety concerns were identified, although low-grade adverse events at the injection site occurred, most prominently at the highest dose, according to the company.

Study follow-up has been extended to 1 year. Patient enrollment continues in the multiple-ascending dose portion of the phase 1 study in patients with high Lp(a) and a confirmed history of stable atherosclerotic cardiovascular disease, the company statement notes.

Detailed results from APOLLO will be presented in a late-breaking clinical trials session at the American College of Cardiology Annual Scientific Session on April 3 by principal investigator Steven E. Nissen, MD, Cleveland Clinic.

A version of this article first appeared on Medscape.com.

Topline results from the phase 1 APOLLO study of SLN360, a short interfering ribonucleic acid (siRNA) targeting lipoprotein(a), showed it significantly reduced Lp(a) in a dose-dependent manner from 46% to up to 98%.

Reductions of up to 81% were maintained out to 150 days, according to a release from the developer of the drug, Silence Therapeutics.

High Lp(a) affects about one in five people worldwide and is a genetic risk factor for cardiovascular disease. There are no approved medications that selectively lower Lp(a), and levels cannot be significantly modified through lifestyle changes or any approved medications.

SLN360 is a siRNA that is designed to lower Lp(a) production by using the body’s natural process of RNA interference to target and silence messenger RNA transcribed from the LPA gene in liver cells.

The first-in-human APOLLO trial evaluated 32 patients with serum Lp(a) concentrations of at least 150 nmol/L and no cardiovascular disease who received a single subcutaneous dose of SLN360 (30 mg, 100 mg, less than or equal to 300 mg, or less than or equal to 600 mg) or placebo and were followed for up to 150 days.

No clinically important safety concerns were identified, although low-grade adverse events at the injection site occurred, most prominently at the highest dose, according to the company.

Study follow-up has been extended to 1 year. Patient enrollment continues in the multiple-ascending dose portion of the phase 1 study in patients with high Lp(a) and a confirmed history of stable atherosclerotic cardiovascular disease, the company statement notes.

Detailed results from APOLLO will be presented in a late-breaking clinical trials session at the American College of Cardiology Annual Scientific Session on April 3 by principal investigator Steven E. Nissen, MD, Cleveland Clinic.

A version of this article first appeared on Medscape.com.

Standard dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor for 12 months after stenting for an acute coronary syndrome (ACS) is under increasing fire from studies showing that varying the duration and intensity of DAPT can reduce bleeding risk without compromising ischemic protection.

A novel meta-analysis of 29 studies indirectly compares short DAPT and de-escalation in 50,602 patients, providing new insights into the relative safety and efficacy of the two strategies and further challenging current guideline recommendations.

Bruce Jancin/MDedge News

Results show no difference in the risk of death between short DAPT with aspirin or P2Y12 inhibitor discontinuation 1-6 months after percutaneous coronary intervention and de-escalation to clopidogrel (Plavix) or lower-dose prasugrel (Effient) or ticagrelor (Brilinta) after the initial high-risk period for ischemic events (risk ratio, 0.98).

“However, there are some differentiating characteristics between the two. De-escalation seems to reduce NACE – net adverse cardiovascular events – likely because of a reduction in major adverse cardiac events, while short DAPT decreases bleeding,” senior author Davide Capodanno, MD, PhD, University of Catania (Italy) told this news organization.

The findings, published in JACC: Cardiovascular Interventions, are clinically plausible because patients remain on two antiplatelet drugs with de-escalation, but are on only one drug at the point of shortening DAPT, he said. “So, of course, if you have only one antiplatelet drug instead of two, you reduce bleeding. On the other hand, having two antiplatelets probably reduces the thrombotic and ischemic events.”

The study failed to show statistically significant differences in ischemic endpoints between strategies, likely because of few events and wide confidence intervals, Dr. Capodanno said. “In fact, when we look at each single component of this NACE, we see a directional difference in favor of de-escalation, which is what you would expect from two drugs.”

All-cause death was also similar among strategies in an alternative five-node analysis that split short DAPT and de-escalation into four groups and included standard DAPT.

Compared with short DAPT with P2Y12 inhibitor discontinuation, both de-escalation to clopidogrel and to half-dose prasugrel or ticagrelor reduced the risk for NACE. De-escalation to half dose also reduced the risk for minor bleeding, compared with short DAPT with aspirin discontinuation.

The overall results were similar in multiple sensitivity analyses and a Bayesian meta-analysis, according to the authors, led by Claudio Laudani, MD, also with the University of Catania.

The Bayesian analysis suggested a greater than 95% probability that de-escalation is the best strategy for NACE, MI, stroke, stent thrombosis, and minor bleeding, whereas short DAPT ranks first for major bleeding with a greater than 95% probability.
 

Guidelines upside down?

In the absence of a head-to-head comparison, the authors say the results warrant a change in current guidelines, which give a class 2a recommendation for short DAPT and a weak class 2b for de-escalation.

“The two strategies have both merits and caveats but, overall, they are very similar; so this is why we believe they should be similar [in status],” Dr. Capodanno said.

In an accompanying editorial, Dean Kereiakes, MD, Christ Hospital Heart and Vascular Center, Cincinnati, and Robert Yeh, MD, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, suggest the guideline recommendations are upside down.

“The class 1 recommendation should be for short DAPT or DAPT de-escalation vs. standard DAPT based on this meta-analysis and, frankly, based on the independent analyses from Bangalore [et al.] and from Shoji [et al.],” Dr. Kereiakes told this news organization.

“When you look at the meta-analyses that have been done, what you see is a reduction of bleeding and either no change or a slight numeric reduction in ischemic events, which magnifies the net clinical benefit, favoring short DAPT or DAPT de-escalation in comparison to standard 12-month, guideline-compliant DAPT,” he said. “So for me, it’s kind of like, game over. When will the guidelines catch up?”

In a comment, Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in an email that “both approaches warrant a class 1 recommendation in patients at high bleeding risk, and both a 2a in non–high bleeding risk patients. With contemporary drug-eluting stents, the prognosis is more strongly determined by bleeding risk and the occurrence of hemorrhagic complications than ischemic risk.”
 

Not all strategies are ‘created equal’

The editorialists caution that, while viable, not all short DAPT or de-escalation strategies are “created equal.” In the five-node analysis, for example, the relative risk of stent thrombosis is highest following a short DAPT regimen with extended aspirin monotherapy (RR, 1.45) and lowest following de-escalation to half-dose prasugrel/ticagrelor (RR, 0.45).

Although not universally observed, the signal of harm with aspirin is consistent with studies such as TWILIGHT, HOST EXAM, and a 2020 meta-analysis, in which stopping aspirin 1-3 months after PCI cut bleeding by 50%, compared with DAPT in patients with ACS, noted Dr. Kereiakes.

He also hinted that more data are forthcoming showing that short DAPT followed by aspirin single-antiplatelet therapy (SAPT) has relatively higher ischemic and bleeding event rates, compared with short DAPT followed by P2Y12 SAPT, with or without an anticoagulant on board.

The key going forward, all agree, is to formally incorporate ischemic/bleeding risk stratification tools into practice guidelines to allow personalized antiplatelet therapy. To that end, Dr. Kereiakes and Dr. Yeh offer a detailed graphic of rank-order recommendations for each strategy by clinical risk strata, with de-escalation generally best for those at greatest ischemic risk and short DAPT best applied to those at greatest bleeding risk.

“The biggest incremental knowledge provided by Davide and Laudani is that they gave us more insight into the granularity of platelet inhibition strategies,” Dr. Kereiakes said. “And it is mechanistically possible to be applied in clinical practice. It’s what I personally see in high-volume clinical practice.”

Before it can be determined which of these strategies is safer and/or more effective, a large, direct head-to-head comparative randomized trial is necessary, Dr. Stone cautioned.

“There are still many variables that were not adjusted for in this excellent study, including the timing of DAPT discontinuation or de-escalation, the specific agent used, etc.,” he added. “Finally, as implied by these results, the optimal regimen may vary based on the balance of ischemic and bleeding risk. Thus, the specific population enrolled in such a randomized trial might importantly affect its outcome.”

As a man “who likes science and statistics,” Dr. Capodanno said he’d also like a large, randomized trial directly comparing the two strategies to confirm these indirect findings. “But it’s very difficult to imagine the power for a trial like that, so it’s not something that’s easy to do.”

Dr. Capodanno reports consulting and speaker fees from Amgen, Arena, Biotronik, Daiichi-Sankyo, and Sanofi outside the present work. Coauthor disclosures are listed in the original article. Dr. Kereiakes reports consulting fees from SINO Medical Sciences Technologies, Svelte Medical Systems, Elixir Medical, and Caliber Therapeutics/Orchestra Biomed. Dr. Yeh reports consulting fees and grant support from Abbott Vascular, AstraZeneca, Boston Scientific, and Medtronic. Dr. Stone reported having no disclosures relevant to the study.

A version of this article first appeared on Medscape.com.

Standard dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor for 12 months after stenting for an acute coronary syndrome (ACS) is under increasing fire from studies showing that varying the duration and intensity of DAPT can reduce bleeding risk without compromising ischemic protection.

A novel meta-analysis of 29 studies indirectly compares short DAPT and de-escalation in 50,602 patients, providing new insights into the relative safety and efficacy of the two strategies and further challenging current guideline recommendations.

Bruce Jancin/MDedge News

Results show no difference in the risk of death between short DAPT with aspirin or P2Y12 inhibitor discontinuation 1-6 months after percutaneous coronary intervention and de-escalation to clopidogrel (Plavix) or lower-dose prasugrel (Effient) or ticagrelor (Brilinta) after the initial high-risk period for ischemic events (risk ratio, 0.98).

“However, there are some differentiating characteristics between the two. De-escalation seems to reduce NACE – net adverse cardiovascular events – likely because of a reduction in major adverse cardiac events, while short DAPT decreases bleeding,” senior author Davide Capodanno, MD, PhD, University of Catania (Italy) told this news organization.

The findings, published in JACC: Cardiovascular Interventions, are clinically plausible because patients remain on two antiplatelet drugs with de-escalation, but are on only one drug at the point of shortening DAPT, he said. “So, of course, if you have only one antiplatelet drug instead of two, you reduce bleeding. On the other hand, having two antiplatelets probably reduces the thrombotic and ischemic events.”

The study failed to show statistically significant differences in ischemic endpoints between strategies, likely because of few events and wide confidence intervals, Dr. Capodanno said. “In fact, when we look at each single component of this NACE, we see a directional difference in favor of de-escalation, which is what you would expect from two drugs.”

All-cause death was also similar among strategies in an alternative five-node analysis that split short DAPT and de-escalation into four groups and included standard DAPT.

Compared with short DAPT with P2Y12 inhibitor discontinuation, both de-escalation to clopidogrel and to half-dose prasugrel or ticagrelor reduced the risk for NACE. De-escalation to half dose also reduced the risk for minor bleeding, compared with short DAPT with aspirin discontinuation.

The overall results were similar in multiple sensitivity analyses and a Bayesian meta-analysis, according to the authors, led by Claudio Laudani, MD, also with the University of Catania.

The Bayesian analysis suggested a greater than 95% probability that de-escalation is the best strategy for NACE, MI, stroke, stent thrombosis, and minor bleeding, whereas short DAPT ranks first for major bleeding with a greater than 95% probability.
 

Guidelines upside down?

In the absence of a head-to-head comparison, the authors say the results warrant a change in current guidelines, which give a class 2a recommendation for short DAPT and a weak class 2b for de-escalation.

“The two strategies have both merits and caveats but, overall, they are very similar; so this is why we believe they should be similar [in status],” Dr. Capodanno said.

In an accompanying editorial, Dean Kereiakes, MD, Christ Hospital Heart and Vascular Center, Cincinnati, and Robert Yeh, MD, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, suggest the guideline recommendations are upside down.

“The class 1 recommendation should be for short DAPT or DAPT de-escalation vs. standard DAPT based on this meta-analysis and, frankly, based on the independent analyses from Bangalore [et al.] and from Shoji [et al.],” Dr. Kereiakes told this news organization.

“When you look at the meta-analyses that have been done, what you see is a reduction of bleeding and either no change or a slight numeric reduction in ischemic events, which magnifies the net clinical benefit, favoring short DAPT or DAPT de-escalation in comparison to standard 12-month, guideline-compliant DAPT,” he said. “So for me, it’s kind of like, game over. When will the guidelines catch up?”

In a comment, Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in an email that “both approaches warrant a class 1 recommendation in patients at high bleeding risk, and both a 2a in non–high bleeding risk patients. With contemporary drug-eluting stents, the prognosis is more strongly determined by bleeding risk and the occurrence of hemorrhagic complications than ischemic risk.”
 

Not all strategies are ‘created equal’

The editorialists caution that, while viable, not all short DAPT or de-escalation strategies are “created equal.” In the five-node analysis, for example, the relative risk of stent thrombosis is highest following a short DAPT regimen with extended aspirin monotherapy (RR, 1.45) and lowest following de-escalation to half-dose prasugrel/ticagrelor (RR, 0.45).

Although not universally observed, the signal of harm with aspirin is consistent with studies such as TWILIGHT, HOST EXAM, and a 2020 meta-analysis, in which stopping aspirin 1-3 months after PCI cut bleeding by 50%, compared with DAPT in patients with ACS, noted Dr. Kereiakes.

He also hinted that more data are forthcoming showing that short DAPT followed by aspirin single-antiplatelet therapy (SAPT) has relatively higher ischemic and bleeding event rates, compared with short DAPT followed by P2Y12 SAPT, with or without an anticoagulant on board.

The key going forward, all agree, is to formally incorporate ischemic/bleeding risk stratification tools into practice guidelines to allow personalized antiplatelet therapy. To that end, Dr. Kereiakes and Dr. Yeh offer a detailed graphic of rank-order recommendations for each strategy by clinical risk strata, with de-escalation generally best for those at greatest ischemic risk and short DAPT best applied to those at greatest bleeding risk.

“The biggest incremental knowledge provided by Davide and Laudani is that they gave us more insight into the granularity of platelet inhibition strategies,” Dr. Kereiakes said. “And it is mechanistically possible to be applied in clinical practice. It’s what I personally see in high-volume clinical practice.”

Before it can be determined which of these strategies is safer and/or more effective, a large, direct head-to-head comparative randomized trial is necessary, Dr. Stone cautioned.

“There are still many variables that were not adjusted for in this excellent study, including the timing of DAPT discontinuation or de-escalation, the specific agent used, etc.,” he added. “Finally, as implied by these results, the optimal regimen may vary based on the balance of ischemic and bleeding risk. Thus, the specific population enrolled in such a randomized trial might importantly affect its outcome.”

As a man “who likes science and statistics,” Dr. Capodanno said he’d also like a large, randomized trial directly comparing the two strategies to confirm these indirect findings. “But it’s very difficult to imagine the power for a trial like that, so it’s not something that’s easy to do.”

Dr. Capodanno reports consulting and speaker fees from Amgen, Arena, Biotronik, Daiichi-Sankyo, and Sanofi outside the present work. Coauthor disclosures are listed in the original article. Dr. Kereiakes reports consulting fees from SINO Medical Sciences Technologies, Svelte Medical Systems, Elixir Medical, and Caliber Therapeutics/Orchestra Biomed. Dr. Yeh reports consulting fees and grant support from Abbott Vascular, AstraZeneca, Boston Scientific, and Medtronic. Dr. Stone reported having no disclosures relevant to the study.

A version of this article first appeared on Medscape.com.

Standard dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor for 12 months after stenting for an acute coronary syndrome (ACS) is under increasing fire from studies showing that varying the duration and intensity of DAPT can reduce bleeding risk without compromising ischemic protection.

A novel meta-analysis of 29 studies indirectly compares short DAPT and de-escalation in 50,602 patients, providing new insights into the relative safety and efficacy of the two strategies and further challenging current guideline recommendations.

Bruce Jancin/MDedge News

Results show no difference in the risk of death between short DAPT with aspirin or P2Y12 inhibitor discontinuation 1-6 months after percutaneous coronary intervention and de-escalation to clopidogrel (Plavix) or lower-dose prasugrel (Effient) or ticagrelor (Brilinta) after the initial high-risk period for ischemic events (risk ratio, 0.98).

“However, there are some differentiating characteristics between the two. De-escalation seems to reduce NACE – net adverse cardiovascular events – likely because of a reduction in major adverse cardiac events, while short DAPT decreases bleeding,” senior author Davide Capodanno, MD, PhD, University of Catania (Italy) told this news organization.

The findings, published in JACC: Cardiovascular Interventions, are clinically plausible because patients remain on two antiplatelet drugs with de-escalation, but are on only one drug at the point of shortening DAPT, he said. “So, of course, if you have only one antiplatelet drug instead of two, you reduce bleeding. On the other hand, having two antiplatelets probably reduces the thrombotic and ischemic events.”

The study failed to show statistically significant differences in ischemic endpoints between strategies, likely because of few events and wide confidence intervals, Dr. Capodanno said. “In fact, when we look at each single component of this NACE, we see a directional difference in favor of de-escalation, which is what you would expect from two drugs.”

All-cause death was also similar among strategies in an alternative five-node analysis that split short DAPT and de-escalation into four groups and included standard DAPT.

Compared with short DAPT with P2Y12 inhibitor discontinuation, both de-escalation to clopidogrel and to half-dose prasugrel or ticagrelor reduced the risk for NACE. De-escalation to half dose also reduced the risk for minor bleeding, compared with short DAPT with aspirin discontinuation.

The overall results were similar in multiple sensitivity analyses and a Bayesian meta-analysis, according to the authors, led by Claudio Laudani, MD, also with the University of Catania.

The Bayesian analysis suggested a greater than 95% probability that de-escalation is the best strategy for NACE, MI, stroke, stent thrombosis, and minor bleeding, whereas short DAPT ranks first for major bleeding with a greater than 95% probability.
 

Guidelines upside down?

In the absence of a head-to-head comparison, the authors say the results warrant a change in current guidelines, which give a class 2a recommendation for short DAPT and a weak class 2b for de-escalation.

“The two strategies have both merits and caveats but, overall, they are very similar; so this is why we believe they should be similar [in status],” Dr. Capodanno said.

In an accompanying editorial, Dean Kereiakes, MD, Christ Hospital Heart and Vascular Center, Cincinnati, and Robert Yeh, MD, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, suggest the guideline recommendations are upside down.

“The class 1 recommendation should be for short DAPT or DAPT de-escalation vs. standard DAPT based on this meta-analysis and, frankly, based on the independent analyses from Bangalore [et al.] and from Shoji [et al.],” Dr. Kereiakes told this news organization.

“When you look at the meta-analyses that have been done, what you see is a reduction of bleeding and either no change or a slight numeric reduction in ischemic events, which magnifies the net clinical benefit, favoring short DAPT or DAPT de-escalation in comparison to standard 12-month, guideline-compliant DAPT,” he said. “So for me, it’s kind of like, game over. When will the guidelines catch up?”

In a comment, Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in an email that “both approaches warrant a class 1 recommendation in patients at high bleeding risk, and both a 2a in non–high bleeding risk patients. With contemporary drug-eluting stents, the prognosis is more strongly determined by bleeding risk and the occurrence of hemorrhagic complications than ischemic risk.”
 

Not all strategies are ‘created equal’

The editorialists caution that, while viable, not all short DAPT or de-escalation strategies are “created equal.” In the five-node analysis, for example, the relative risk of stent thrombosis is highest following a short DAPT regimen with extended aspirin monotherapy (RR, 1.45) and lowest following de-escalation to half-dose prasugrel/ticagrelor (RR, 0.45).

Although not universally observed, the signal of harm with aspirin is consistent with studies such as TWILIGHT, HOST EXAM, and a 2020 meta-analysis, in which stopping aspirin 1-3 months after PCI cut bleeding by 50%, compared with DAPT in patients with ACS, noted Dr. Kereiakes.

He also hinted that more data are forthcoming showing that short DAPT followed by aspirin single-antiplatelet therapy (SAPT) has relatively higher ischemic and bleeding event rates, compared with short DAPT followed by P2Y12 SAPT, with or without an anticoagulant on board.

The key going forward, all agree, is to formally incorporate ischemic/bleeding risk stratification tools into practice guidelines to allow personalized antiplatelet therapy. To that end, Dr. Kereiakes and Dr. Yeh offer a detailed graphic of rank-order recommendations for each strategy by clinical risk strata, with de-escalation generally best for those at greatest ischemic risk and short DAPT best applied to those at greatest bleeding risk.

“The biggest incremental knowledge provided by Davide and Laudani is that they gave us more insight into the granularity of platelet inhibition strategies,” Dr. Kereiakes said. “And it is mechanistically possible to be applied in clinical practice. It’s what I personally see in high-volume clinical practice.”

Before it can be determined which of these strategies is safer and/or more effective, a large, direct head-to-head comparative randomized trial is necessary, Dr. Stone cautioned.

“There are still many variables that were not adjusted for in this excellent study, including the timing of DAPT discontinuation or de-escalation, the specific agent used, etc.,” he added. “Finally, as implied by these results, the optimal regimen may vary based on the balance of ischemic and bleeding risk. Thus, the specific population enrolled in such a randomized trial might importantly affect its outcome.”

As a man “who likes science and statistics,” Dr. Capodanno said he’d also like a large, randomized trial directly comparing the two strategies to confirm these indirect findings. “But it’s very difficult to imagine the power for a trial like that, so it’s not something that’s easy to do.”

Dr. Capodanno reports consulting and speaker fees from Amgen, Arena, Biotronik, Daiichi-Sankyo, and Sanofi outside the present work. Coauthor disclosures are listed in the original article. Dr. Kereiakes reports consulting fees from SINO Medical Sciences Technologies, Svelte Medical Systems, Elixir Medical, and Caliber Therapeutics/Orchestra Biomed. Dr. Yeh reports consulting fees and grant support from Abbott Vascular, AstraZeneca, Boston Scientific, and Medtronic. Dr. Stone reported having no disclosures relevant to the study.

A version of this article first appeared on Medscape.com.

People who have had COVID-19 have an increased risk for, and 12-month burden of, cardiovascular disease (CVD) that is substantial and spans an array of cardiovascular disorders, a deep dive into federal data suggests.

“I went into this thinking that this is most likely happening in people to start with who have a higher risk of cardiovascular disorders, smokers, people with high BMI, diabetes, but what we found is something different,” Ziyad Al-Aly, MD, said in an interview. “It’s evident in people at high risk, but it was also as clear as the sun even in people who have no cardiovascular risk whatsoever.”

Rates were increased in younger adults, never smokers, White and Black people, and males and females, he said. “So the risk confirmed by the SARS-CoV-2 virus seems to spare almost no one.”

Although cardiovascular outcomes increased with the severity of the acute infection, the excess risks and burdens were also evident in those who never required hospitalization, a group that represents the majority of people with COVID-19, observed Dr. Al-Aly, who directs the Clinical Epidemiology Center at the Veterans Affairs St. Louis Health Care System.

“This study is very important because it underscores not just the acute cardiovascular risk associated with COVID but the increased risk of chronic cardiovascular outcomes as well,” cardiologist C. Michael Gibson, MD, professor of medicine, Harvard Medical School, Boston, said in an interview. “Given the number of patients in the U.S. who have been infected with COVID, this could represent a significant chronic burden on the health care system, particularly as health care professionals leave the profession.”

For the study, the investigators used national VA databases to build a cohort of 153,760 veterans who were alive 30 days after testing positive for COVID-19 between March 1, 2020, and January 2021. They were compared with a contemporary cohort of 5.6 million veterans with no evidence of SARS-CoV-2 infection and a historical cohort of 5.8 million veterans using the system in 2017 prior to the pandemic. Median follow-up was 347, 348, and 347 days, respectively.

As reported in Nature Medicine, the risk for a major adverse cardiovascular event, a composite of myocardial infarction, stroke, and all-cause mortality, was 4% higher in people who had been infected with COVID-19 than in those who had not.

“People say 4% is small, but actually it’s really, really big if you think about it in the context of the huge number of people who have had COVID-19 in the United States, and also globally,” Dr. Al-Aly said.

Compared with the contemporary control group, people who had COVID-19 had an increased risk (hazard ratio [HR]) and burden per 1,000 people at 1 year for the following cardiovascular outcomes:

• Stroke: HR, 1.52; burden, 4.03
• Transient ischemic attack: HR, 1.49; burden, 1.84
• Dysrhythmias: HR, 1.69; burden, 19.86
• Ischemic heart disease: HR, 1.66; burden, 7.28
• Heart failure: HR, 1.72; burden, 11.61
• Nonischemic cardiomyopathy: HR, 1.62; burden 3.56
• Pulmonary embolism: HR, 2.93; burden, 5.47
• Deep vein thrombosis: HR, 2.09; burden, 4.18
• Pericarditis: HR, 1.85, burden, 0.98
• Myocarditis: HR, 5.38; burden, 0.31

Recent reports have raised concerns about an association between COVID-19 vaccines and myocarditis and pericarditis, particularly in young males. Although very few of the participants were vaccinated prior to becoming infected, as vaccines were not yet widely available, the researchers performed two analyses censoring participants at the time of the first dose of any COVID-19 vaccine and adjusting for vaccination as a time-varying covariate.

The absolute numbers of myocarditis and pericarditis were still higher than the contemporary and historical cohorts. These numbers are much larger than those reported for myocarditis after vaccines, which are generally around 40 cases per 1 million people, observed Dr. Al-Aly.

The overall results were also consistent when compared with the historical control subjects.

“What we’re seeing in our report and others is that SARS-CoV-2 can leave a sort of scar or imprint on people, and some of these conditions are likely chronic conditions,” Dr. Al-Aly said. “So you’re going to have a generation of people who will bear the scar of COVID for their lifetime and I think that requires recognition and attention, so we’re aware of the magnitude of the problem and prepared to deal with it.”

With more than 76 million COVID-19 cases in the United States, that effort will likely have to be at the federal level, similar to President Joe Biden’s recent relaunch of the “Cancer Moonshot,” he added. “We need a greater and broader recognition at the federal level to try and recognize that when you have an earthquake, you don’t just deal with the earthquake when the earth is shaking, but you also need to deal with the aftermath.”

Dr. Gibson pointed out that this was a study of predominantly males and, thus, it’s unclear if the results can be extended to females. Nevertheless, he added, “long COVID may include outcomes beyond the central nervous system and we should educate patients about the risk of late cardiovascular outcomes.”

The authors noted the largely White, male cohort may limit generalizability of the findings. Other limitations include the possibility that some people may have had COVID-19 but were not tested, the datasets lacked information on cause of death, and possible residual confounding not accounted for in the adjusted analyses.

The research was funded by the U.S. Department of Veterans Affairs and two American Society of Nephrology and Kidney Cure fellowship awards. The authors declared no competing interests. Dr. Gibson reports having no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

People who have had COVID-19 have an increased risk for, and 12-month burden of, cardiovascular disease (CVD) that is substantial and spans an array of cardiovascular disorders, a deep dive into federal data suggests.

“I went into this thinking that this is most likely happening in people to start with who have a higher risk of cardiovascular disorders, smokers, people with high BMI, diabetes, but what we found is something different,” Ziyad Al-Aly, MD, said in an interview. “It’s evident in people at high risk, but it was also as clear as the sun even in people who have no cardiovascular risk whatsoever.”

Rates were increased in younger adults, never smokers, White and Black people, and males and females, he said. “So the risk confirmed by the SARS-CoV-2 virus seems to spare almost no one.”

Although cardiovascular outcomes increased with the severity of the acute infection, the excess risks and burdens were also evident in those who never required hospitalization, a group that represents the majority of people with COVID-19, observed Dr. Al-Aly, who directs the Clinical Epidemiology Center at the Veterans Affairs St. Louis Health Care System.

“This study is very important because it underscores not just the acute cardiovascular risk associated with COVID but the increased risk of chronic cardiovascular outcomes as well,” cardiologist C. Michael Gibson, MD, professor of medicine, Harvard Medical School, Boston, said in an interview. “Given the number of patients in the U.S. who have been infected with COVID, this could represent a significant chronic burden on the health care system, particularly as health care professionals leave the profession.”

For the study, the investigators used national VA databases to build a cohort of 153,760 veterans who were alive 30 days after testing positive for COVID-19 between March 1, 2020, and January 2021. They were compared with a contemporary cohort of 5.6 million veterans with no evidence of SARS-CoV-2 infection and a historical cohort of 5.8 million veterans using the system in 2017 prior to the pandemic. Median follow-up was 347, 348, and 347 days, respectively.

As reported in Nature Medicine, the risk for a major adverse cardiovascular event, a composite of myocardial infarction, stroke, and all-cause mortality, was 4% higher in people who had been infected with COVID-19 than in those who had not.

“People say 4% is small, but actually it’s really, really big if you think about it in the context of the huge number of people who have had COVID-19 in the United States, and also globally,” Dr. Al-Aly said.

Compared with the contemporary control group, people who had COVID-19 had an increased risk (hazard ratio [HR]) and burden per 1,000 people at 1 year for the following cardiovascular outcomes:

• Stroke: HR, 1.52; burden, 4.03
• Transient ischemic attack: HR, 1.49; burden, 1.84
• Dysrhythmias: HR, 1.69; burden, 19.86
• Ischemic heart disease: HR, 1.66; burden, 7.28
• Heart failure: HR, 1.72; burden, 11.61
• Nonischemic cardiomyopathy: HR, 1.62; burden 3.56
• Pulmonary embolism: HR, 2.93; burden, 5.47
• Deep vein thrombosis: HR, 2.09; burden, 4.18
• Pericarditis: HR, 1.85, burden, 0.98
• Myocarditis: HR, 5.38; burden, 0.31

Recent reports have raised concerns about an association between COVID-19 vaccines and myocarditis and pericarditis, particularly in young males. Although very few of the participants were vaccinated prior to becoming infected, as vaccines were not yet widely available, the researchers performed two analyses censoring participants at the time of the first dose of any COVID-19 vaccine and adjusting for vaccination as a time-varying covariate.

The absolute numbers of myocarditis and pericarditis were still higher than the contemporary and historical cohorts. These numbers are much larger than those reported for myocarditis after vaccines, which are generally around 40 cases per 1 million people, observed Dr. Al-Aly.

The overall results were also consistent when compared with the historical control subjects.

“What we’re seeing in our report and others is that SARS-CoV-2 can leave a sort of scar or imprint on people, and some of these conditions are likely chronic conditions,” Dr. Al-Aly said. “So you’re going to have a generation of people who will bear the scar of COVID for their lifetime and I think that requires recognition and attention, so we’re aware of the magnitude of the problem and prepared to deal with it.”

With more than 76 million COVID-19 cases in the United States, that effort will likely have to be at the federal level, similar to President Joe Biden’s recent relaunch of the “Cancer Moonshot,” he added. “We need a greater and broader recognition at the federal level to try and recognize that when you have an earthquake, you don’t just deal with the earthquake when the earth is shaking, but you also need to deal with the aftermath.”

Dr. Gibson pointed out that this was a study of predominantly males and, thus, it’s unclear if the results can be extended to females. Nevertheless, he added, “long COVID may include outcomes beyond the central nervous system and we should educate patients about the risk of late cardiovascular outcomes.”

The authors noted the largely White, male cohort may limit generalizability of the findings. Other limitations include the possibility that some people may have had COVID-19 but were not tested, the datasets lacked information on cause of death, and possible residual confounding not accounted for in the adjusted analyses.

The research was funded by the U.S. Department of Veterans Affairs and two American Society of Nephrology and Kidney Cure fellowship awards. The authors declared no competing interests. Dr. Gibson reports having no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

People who have had COVID-19 have an increased risk for, and 12-month burden of, cardiovascular disease (CVD) that is substantial and spans an array of cardiovascular disorders, a deep dive into federal data suggests.

“I went into this thinking that this is most likely happening in people to start with who have a higher risk of cardiovascular disorders, smokers, people with high BMI, diabetes, but what we found is something different,” Ziyad Al-Aly, MD, said in an interview. “It’s evident in people at high risk, but it was also as clear as the sun even in people who have no cardiovascular risk whatsoever.”

Rates were increased in younger adults, never smokers, White and Black people, and males and females, he said. “So the risk confirmed by the SARS-CoV-2 virus seems to spare almost no one.”

Although cardiovascular outcomes increased with the severity of the acute infection, the excess risks and burdens were also evident in those who never required hospitalization, a group that represents the majority of people with COVID-19, observed Dr. Al-Aly, who directs the Clinical Epidemiology Center at the Veterans Affairs St. Louis Health Care System.

“This study is very important because it underscores not just the acute cardiovascular risk associated with COVID but the increased risk of chronic cardiovascular outcomes as well,” cardiologist C. Michael Gibson, MD, professor of medicine, Harvard Medical School, Boston, said in an interview. “Given the number of patients in the U.S. who have been infected with COVID, this could represent a significant chronic burden on the health care system, particularly as health care professionals leave the profession.”

For the study, the investigators used national VA databases to build a cohort of 153,760 veterans who were alive 30 days after testing positive for COVID-19 between March 1, 2020, and January 2021. They were compared with a contemporary cohort of 5.6 million veterans with no evidence of SARS-CoV-2 infection and a historical cohort of 5.8 million veterans using the system in 2017 prior to the pandemic. Median follow-up was 347, 348, and 347 days, respectively.

As reported in Nature Medicine, the risk for a major adverse cardiovascular event, a composite of myocardial infarction, stroke, and all-cause mortality, was 4% higher in people who had been infected with COVID-19 than in those who had not.

“People say 4% is small, but actually it’s really, really big if you think about it in the context of the huge number of people who have had COVID-19 in the United States, and also globally,” Dr. Al-Aly said.

Compared with the contemporary control group, people who had COVID-19 had an increased risk (hazard ratio [HR]) and burden per 1,000 people at 1 year for the following cardiovascular outcomes:

• Stroke: HR, 1.52; burden, 4.03
• Transient ischemic attack: HR, 1.49; burden, 1.84
• Dysrhythmias: HR, 1.69; burden, 19.86
• Ischemic heart disease: HR, 1.66; burden, 7.28
• Heart failure: HR, 1.72; burden, 11.61
• Nonischemic cardiomyopathy: HR, 1.62; burden 3.56
• Pulmonary embolism: HR, 2.93; burden, 5.47
• Deep vein thrombosis: HR, 2.09; burden, 4.18
• Pericarditis: HR, 1.85, burden, 0.98
• Myocarditis: HR, 5.38; burden, 0.31

Recent reports have raised concerns about an association between COVID-19 vaccines and myocarditis and pericarditis, particularly in young males. Although very few of the participants were vaccinated prior to becoming infected, as vaccines were not yet widely available, the researchers performed two analyses censoring participants at the time of the first dose of any COVID-19 vaccine and adjusting for vaccination as a time-varying covariate.

The absolute numbers of myocarditis and pericarditis were still higher than the contemporary and historical cohorts. These numbers are much larger than those reported for myocarditis after vaccines, which are generally around 40 cases per 1 million people, observed Dr. Al-Aly.

The overall results were also consistent when compared with the historical control subjects.

“What we’re seeing in our report and others is that SARS-CoV-2 can leave a sort of scar or imprint on people, and some of these conditions are likely chronic conditions,” Dr. Al-Aly said. “So you’re going to have a generation of people who will bear the scar of COVID for their lifetime and I think that requires recognition and attention, so we’re aware of the magnitude of the problem and prepared to deal with it.”

With more than 76 million COVID-19 cases in the United States, that effort will likely have to be at the federal level, similar to President Joe Biden’s recent relaunch of the “Cancer Moonshot,” he added. “We need a greater and broader recognition at the federal level to try and recognize that when you have an earthquake, you don’t just deal with the earthquake when the earth is shaking, but you also need to deal with the aftermath.”

Dr. Gibson pointed out that this was a study of predominantly males and, thus, it’s unclear if the results can be extended to females. Nevertheless, he added, “long COVID may include outcomes beyond the central nervous system and we should educate patients about the risk of late cardiovascular outcomes.”

The authors noted the largely White, male cohort may limit generalizability of the findings. Other limitations include the possibility that some people may have had COVID-19 but were not tested, the datasets lacked information on cause of death, and possible residual confounding not accounted for in the adjusted analyses.

The research was funded by the U.S. Department of Veterans Affairs and two American Society of Nephrology and Kidney Cure fellowship awards. The authors declared no competing interests. Dr. Gibson reports having no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

Nearly one-third of adults over age 65 developed one or more new medical conditions in the weeks following a COVID-19 infection, according to new research.

The findings of the observational study, which were published in the BMJ, show the risk of a new condition being triggered by COVID is more than twice as high in seniors, compared with younger patients. Plus, the researchers observed an even higher risk among those who were hospitalized, with nearly half (46%) of patients having developed new conditions after the acute COVID-19 infection period.

Respiratory failure with shortness of breath was the most common postacute sequela, but a wide range of heart, kidney, lung, liver, cognitive, mental health, and other conditions were diagnosed at least 3 weeks after initial infection and persisted beyond 30 days.

This is one of the first studies to specifically describe the incidence and severity of new conditions triggered by COVID-19 infection in a general sample of older adults, said study author Ken Cohen MD, FACP, executive director of translational research at Optum Labs and national senior medical director at Optum Care.

“Much of what has been published on the postacute sequelae of COVID-19 has been predominantly from a younger population, and many of the patients had been hospitalized,” Dr. Cohen noted. “This was the first study to focus on a large population of seniors, most of whom did not require hospitalization.”

Dr. Cohen and colleagues reviewed the health insurance records of more than 133,000 Medicare beneficiaries aged 65 or older who were diagnosed with COVID-19 before April 2020. They also matched individuals by age, race, sex, hospitalization status, and other factors to comparison groups without COVID-19 (one from 2020 and one from 2019), and to a group diagnosed with other lower respiratory tract viral infections before the pandemic.
 

Risk of developing new conditions was higher in hospitalized

After acute COVID-19 infection, 32% of seniors sought medical care for at least one new medical condition in 2020, compared with 21% of uninfected people in the same year.

The most commonly observed conditions included:

• Respiratory failure (7.55% higher risk).
• Fatigue (5.66% higher risk).
• High blood pressure (4.43% higher risk).
• Memory problems (2.63% higher risk).
• Kidney injury (2.59% higher risk).
• Mental health diagnoses (2.5% higher risk).
• Blood-clotting disorders (1.47 % higher risk).
• Heart rhythm disorders (2.9% higher risk).

The risk of developing new conditions was even higher among those 23,486 who were hospitalized in 2020. Those individuals showed a 23.6% higher risk for developing at least one new condition, compared with uninfected seniors in the same year. Also, patients older than 75 had a higher risk for neurological disorders, including dementia, encephalopathy, and memory problems. The researchers also found that respiratory failure and kidney injury were significantly more likely to affect men and Black patients.

When those who had COVID were compared with the group with other lower respiratory viral infections before the pandemic, only the risks of respiratory failure (2.39% higher), dementia (0.71% higher), and fatigue (0.18% higher) were higher.

Primary care providers can learn from these data to better evaluate and manage their geriatric patients with COVID-19 infection, said Amit Shah, MD, a geriatrician with the Mayo Clinic in Phoenix, in an interview.

“We must assess older patients who have had COVID-19 for more than just improvement from the respiratory symptoms of COVID-19 in post-COVID follow-up visits,” he said. “Older individuals with frailty have vulnerability to subsequent complications from severe illnesses and it is common to see post-illness diagnoses, such as new diagnosis of delirium; dementia; or renal, respiratory, or cardiac issues that is precipitated by the original illness. This study confirms that this is likely the case with COVID-19 as well.

“Primary care physicians should be vigilant for these complications, including attention to the rehabilitation needs of older patients with longer-term postviral fatigue from COVID-19,” Dr. Shah added.
 

Data predates ‘Omicron wave’

It remains uncertain whether sequelae will differ with the Omicron variant, but the findings remain applicable, Dr. Cohen said.

“We know that illness from the Omicron variant is on average less severe in those that have been vaccinated. However, throughout the Omicron wave, individuals who have not been vaccinated continue to have significant rates of serious illness and hospitalization,” he said.

“Our findings showed that serious illness with hospitalization was associated with a higher rate of sequelae. It can therefore be inferred that the rates of sequelae seen in our study would continue to occur in unvaccinated individuals who contract Omicron, but might occur less frequently in vaccinated individuals who contract Omicron and have less severe illness.”

Dr. Cohen serves as a consultant for Pfizer. Dr. Shah has disclosed no relevant financial relationships.

Nearly one-third of adults over age 65 developed one or more new medical conditions in the weeks following a COVID-19 infection, according to new research.

The findings of the observational study, which were published in the BMJ, show the risk of a new condition being triggered by COVID is more than twice as high in seniors, compared with younger patients. Plus, the researchers observed an even higher risk among those who were hospitalized, with nearly half (46%) of patients having developed new conditions after the acute COVID-19 infection period.

Respiratory failure with shortness of breath was the most common postacute sequela, but a wide range of heart, kidney, lung, liver, cognitive, mental health, and other conditions were diagnosed at least 3 weeks after initial infection and persisted beyond 30 days.

This is one of the first studies to specifically describe the incidence and severity of new conditions triggered by COVID-19 infection in a general sample of older adults, said study author Ken Cohen MD, FACP, executive director of translational research at Optum Labs and national senior medical director at Optum Care.

“Much of what has been published on the postacute sequelae of COVID-19 has been predominantly from a younger population, and many of the patients had been hospitalized,” Dr. Cohen noted. “This was the first study to focus on a large population of seniors, most of whom did not require hospitalization.”

Dr. Cohen and colleagues reviewed the health insurance records of more than 133,000 Medicare beneficiaries aged 65 or older who were diagnosed with COVID-19 before April 2020. They also matched individuals by age, race, sex, hospitalization status, and other factors to comparison groups without COVID-19 (one from 2020 and one from 2019), and to a group diagnosed with other lower respiratory tract viral infections before the pandemic.
 

Risk of developing new conditions was higher in hospitalized

After acute COVID-19 infection, 32% of seniors sought medical care for at least one new medical condition in 2020, compared with 21% of uninfected people in the same year.

The most commonly observed conditions included:

• Respiratory failure (7.55% higher risk).
• Fatigue (5.66% higher risk).
• High blood pressure (4.43% higher risk).
• Memory problems (2.63% higher risk).
• Kidney injury (2.59% higher risk).
• Mental health diagnoses (2.5% higher risk).
• Blood-clotting disorders (1.47 % higher risk).
• Heart rhythm disorders (2.9% higher risk).

The risk of developing new conditions was even higher among those 23,486 who were hospitalized in 2020. Those individuals showed a 23.6% higher risk for developing at least one new condition, compared with uninfected seniors in the same year. Also, patients older than 75 had a higher risk for neurological disorders, including dementia, encephalopathy, and memory problems. The researchers also found that respiratory failure and kidney injury were significantly more likely to affect men and Black patients.

When those who had COVID were compared with the group with other lower respiratory viral infections before the pandemic, only the risks of respiratory failure (2.39% higher), dementia (0.71% higher), and fatigue (0.18% higher) were higher.

Primary care providers can learn from these data to better evaluate and manage their geriatric patients with COVID-19 infection, said Amit Shah, MD, a geriatrician with the Mayo Clinic in Phoenix, in an interview.

“We must assess older patients who have had COVID-19 for more than just improvement from the respiratory symptoms of COVID-19 in post-COVID follow-up visits,” he said. “Older individuals with frailty have vulnerability to subsequent complications from severe illnesses and it is common to see post-illness diagnoses, such as new diagnosis of delirium; dementia; or renal, respiratory, or cardiac issues that is precipitated by the original illness. This study confirms that this is likely the case with COVID-19 as well.

“Primary care physicians should be vigilant for these complications, including attention to the rehabilitation needs of older patients with longer-term postviral fatigue from COVID-19,” Dr. Shah added.
 

Data predates ‘Omicron wave’

It remains uncertain whether sequelae will differ with the Omicron variant, but the findings remain applicable, Dr. Cohen said.

“We know that illness from the Omicron variant is on average less severe in those that have been vaccinated. However, throughout the Omicron wave, individuals who have not been vaccinated continue to have significant rates of serious illness and hospitalization,” he said.

“Our findings showed that serious illness with hospitalization was associated with a higher rate of sequelae. It can therefore be inferred that the rates of sequelae seen in our study would continue to occur in unvaccinated individuals who contract Omicron, but might occur less frequently in vaccinated individuals who contract Omicron and have less severe illness.”

Dr. Cohen serves as a consultant for Pfizer. Dr. Shah has disclosed no relevant financial relationships.

Nearly one-third of adults over age 65 developed one or more new medical conditions in the weeks following a COVID-19 infection, according to new research.

The findings of the observational study, which were published in the BMJ, show the risk of a new condition being triggered by COVID is more than twice as high in seniors, compared with younger patients. Plus, the researchers observed an even higher risk among those who were hospitalized, with nearly half (46%) of patients having developed new conditions after the acute COVID-19 infection period.

Respiratory failure with shortness of breath was the most common postacute sequela, but a wide range of heart, kidney, lung, liver, cognitive, mental health, and other conditions were diagnosed at least 3 weeks after initial infection and persisted beyond 30 days.

This is one of the first studies to specifically describe the incidence and severity of new conditions triggered by COVID-19 infection in a general sample of older adults, said study author Ken Cohen MD, FACP, executive director of translational research at Optum Labs and national senior medical director at Optum Care.

“Much of what has been published on the postacute sequelae of COVID-19 has been predominantly from a younger population, and many of the patients had been hospitalized,” Dr. Cohen noted. “This was the first study to focus on a large population of seniors, most of whom did not require hospitalization.”

Dr. Cohen and colleagues reviewed the health insurance records of more than 133,000 Medicare beneficiaries aged 65 or older who were diagnosed with COVID-19 before April 2020. They also matched individuals by age, race, sex, hospitalization status, and other factors to comparison groups without COVID-19 (one from 2020 and one from 2019), and to a group diagnosed with other lower respiratory tract viral infections before the pandemic.
 

Risk of developing new conditions was higher in hospitalized

After acute COVID-19 infection, 32% of seniors sought medical care for at least one new medical condition in 2020, compared with 21% of uninfected people in the same year.

The most commonly observed conditions included:

• Respiratory failure (7.55% higher risk).
• Fatigue (5.66% higher risk).
• High blood pressure (4.43% higher risk).
• Memory problems (2.63% higher risk).
• Kidney injury (2.59% higher risk).
• Mental health diagnoses (2.5% higher risk).
• Blood-clotting disorders (1.47 % higher risk).
• Heart rhythm disorders (2.9% higher risk).

The risk of developing new conditions was even higher among those 23,486 who were hospitalized in 2020. Those individuals showed a 23.6% higher risk for developing at least one new condition, compared with uninfected seniors in the same year. Also, patients older than 75 had a higher risk for neurological disorders, including dementia, encephalopathy, and memory problems. The researchers also found that respiratory failure and kidney injury were significantly more likely to affect men and Black patients.

When those who had COVID were compared with the group with other lower respiratory viral infections before the pandemic, only the risks of respiratory failure (2.39% higher), dementia (0.71% higher), and fatigue (0.18% higher) were higher.

Primary care providers can learn from these data to better evaluate and manage their geriatric patients with COVID-19 infection, said Amit Shah, MD, a geriatrician with the Mayo Clinic in Phoenix, in an interview.

“We must assess older patients who have had COVID-19 for more than just improvement from the respiratory symptoms of COVID-19 in post-COVID follow-up visits,” he said. “Older individuals with frailty have vulnerability to subsequent complications from severe illnesses and it is common to see post-illness diagnoses, such as new diagnosis of delirium; dementia; or renal, respiratory, or cardiac issues that is precipitated by the original illness. This study confirms that this is likely the case with COVID-19 as well.

“Primary care physicians should be vigilant for these complications, including attention to the rehabilitation needs of older patients with longer-term postviral fatigue from COVID-19,” Dr. Shah added.
 

Data predates ‘Omicron wave’

It remains uncertain whether sequelae will differ with the Omicron variant, but the findings remain applicable, Dr. Cohen said.

“We know that illness from the Omicron variant is on average less severe in those that have been vaccinated. However, throughout the Omicron wave, individuals who have not been vaccinated continue to have significant rates of serious illness and hospitalization,” he said.

“Our findings showed that serious illness with hospitalization was associated with a higher rate of sequelae. It can therefore be inferred that the rates of sequelae seen in our study would continue to occur in unvaccinated individuals who contract Omicron, but might occur less frequently in vaccinated individuals who contract Omicron and have less severe illness.”

Dr. Cohen serves as a consultant for Pfizer. Dr. Shah has disclosed no relevant financial relationships.

Young women appear to be at a higher risk of ischemic stroke than young men, according to a new systematic review of studies on this topic.

The review included 19 studies that reported on sex-specific stroke incidence among young adults and found that overall, in young adults aged 18-35 years, there were 44% more women with ischemic strokes than men.

This gap narrowed in the age group 35-45 years, for which there was conflicting evidence whether more men or women have ischemic strokes.

“An assertion that young women may be disproportionately at risk of ischemic stroke represents a significant departure from our current scientific understanding and may have important implications about the etiology of ischemic strokes in young adults,” the authors note.

“One of the take-home messages from this study is that stroke happens across the entire age spectrum, including young adults, even if they do not have traditional risk factors,” study coauthor Sharon N. Poisson, MD, associate professor of neurology at the University of Colorado Anschutz Medical Campus, Denver, told this news organization.

“If a young person presents with focal neurological symptoms, the possibility of a stroke should not be discounted just because they may not fit the typical profile of a stroke patient. We need more education of the population that young people – including young women – can have a stroke and that fast action to call emergency services is critical,” she said.  

The study was published online Jan. 24 in the journal Stroke as part of a special “Go Red for Women” spotlight issue.

The researchers note that historically it has been believed that men have a higher incidence of stroke in every age group until very old age. However, recent evidence focused on the young adult age group has reported that there are more young women (ages 18-45) with ischemic strokes compared with young men, suggesting that young women may be disproportionately at risk compared with their male counterparts.

Pointing out that a better understanding of these sex differences is important in implementing strategies that can more effectively prevent and treat strokes in this age group, the researchers conducted the current review to synthesize the updated evidence.

They searched PubMed from January 2008 to July 2021 for relevant studies that were population-based and reported stroke incidence by sex or sex-specific incidence rate ratios of young adults age 45 and younger. Statistical synthesis was performed to estimate sex difference by age group (less than or equal to 35, 35-45 and less than or equal to 45 years) and stroke type.

They found 19 relevant studies, including three that reported on overlapping data, with a total of 69,793 young adults (33,775 women and 36,018 men).   

Nine studies did not show a statistically significant sex difference among young adults less than or equal to 45 years. Three studies found higher rates of ischemic stroke among men among young adults less than or equal to 30 to 35 years. Four studies showed more women with ischemic strokes among young adults less than or equal to 35 years.

Overall, there was an effect of a significantly higher incidence of ischemic stroke in women younger than age 35 years, with an incidence rate ratio (IRR) of 1.44. In the 35- to 45-year age group, there was a nonsignificant sex difference in the rate of ischemic stroke, with a slight trend toward a higher incidence in women (IRR, 1.08).

“In this study the sex difference was not clear in the 35-45 age group. But in the age group of over 45 years we know that men have a higher risk of stroke than women, which is probably related to a higher level of atherosclerotic risk factors,” Dr. Poisson commented.

“Interpreting data on stroke in young people is challenging, as stroke is not so common in this population,” she said. “Combining multiple studies helps, but this also introduces a lot of variability, so we need to interpret these results with some caution. However, this is certainly intriguing data and suggests that something interesting may be going on in young adults,” she added. “These observations give us an initial clue that we need to look further into this issue.”

The study did not look at the possible mechanisms behind the results, as the current data came from administrative datasets that are limited in terms of the information collected.  

But Dr. Poisson noted that the traditional risk factors for stroke are high blood pressure and the usual atherosclerotic factors such as high cholesterol.

“These are normally more common in men than in women, and myocardial infarction is more common in younger men than in younger women. But the observation that young women may have a higher risk of stroke than young men suggests that something different may be going on in the mechanism for stroke.” 

She pointed out that women have some unique risk factors for stroke, including oral contraceptive use, pregnancy, and the postpartum period, particularly pre-eclampsia during pregnancy. In addition, migraine, especially migraine with aura, is associated with an increased stroke risk, and migraine is more common in young women than in young men.  

“We don’t completely understand the role of these risk factors, but they may contribute to the results that we found,” Dr. Poisson commented. “The role of estrogen in stroke is complicated. While estrogen is generally thought to be protective against atherosclerotic risk factors, it also increases risk of clotting, so high estrogen states like pregnancy increase risk of stroke,” she added.  

To better understand what is happening, prospectively collected clinical data on younger patients who have had a stroke are needed. Some such studies are underway, but a concerted effort to do this in a large, multicenter registry would be desirable, Dr. Poisson said.

She noted that the presentation of a stroke in young people would be similar to that in the older population, with the most recent acronym to help recognize stroke symptoms being “BE FAST” – balance, eyes (vision), face (drooping), arm, speech (slurred), time (call emergency services quickly).

Call for more women in clinical trials

In an accompanying commentary, Cheryl Bushnell, MD, professor of neurology at Wake Forest School of Medicine, Winston-Salem, N.C., and Moira Kapral, MD, professor in medicine and health policy at the University of Toronto, say these findings support the need for further study to understand and address the causes and risk factors of stroke in young women.

However, they point out that representation and reporting of women in clinical trials of acute stroke continues to be suboptimal, and they call for improved incorporation of sex and gender into study design, analysis, and interpretation, which they say is critical for producing research that is broadly generalizable and applicable to different populations. 

Coauthor Stacey L. Daugherty, MD, is funded by the National Institutes of Health. Dr. Poisson and Dr. Kapral have disclosed no relevant financial relationships. Dr. Bushnell reports ownership interest in Care Directions.

A version of this article first appeared on Medscape.com.

Young women appear to be at a higher risk of ischemic stroke than young men, according to a new systematic review of studies on this topic.

The review included 19 studies that reported on sex-specific stroke incidence among young adults and found that overall, in young adults aged 18-35 years, there were 44% more women with ischemic strokes than men.

This gap narrowed in the age group 35-45 years, for which there was conflicting evidence whether more men or women have ischemic strokes.

“An assertion that young women may be disproportionately at risk of ischemic stroke represents a significant departure from our current scientific understanding and may have important implications about the etiology of ischemic strokes in young adults,” the authors note.

“One of the take-home messages from this study is that stroke happens across the entire age spectrum, including young adults, even if they do not have traditional risk factors,” study coauthor Sharon N. Poisson, MD, associate professor of neurology at the University of Colorado Anschutz Medical Campus, Denver, told this news organization.

“If a young person presents with focal neurological symptoms, the possibility of a stroke should not be discounted just because they may not fit the typical profile of a stroke patient. We need more education of the population that young people – including young women – can have a stroke and that fast action to call emergency services is critical,” she said.  

The study was published online Jan. 24 in the journal Stroke as part of a special “Go Red for Women” spotlight issue.

The researchers note that historically it has been believed that men have a higher incidence of stroke in every age group until very old age. However, recent evidence focused on the young adult age group has reported that there are more young women (ages 18-45) with ischemic strokes compared with young men, suggesting that young women may be disproportionately at risk compared with their male counterparts.

Pointing out that a better understanding of these sex differences is important in implementing strategies that can more effectively prevent and treat strokes in this age group, the researchers conducted the current review to synthesize the updated evidence.

They searched PubMed from January 2008 to July 2021 for relevant studies that were population-based and reported stroke incidence by sex or sex-specific incidence rate ratios of young adults age 45 and younger. Statistical synthesis was performed to estimate sex difference by age group (less than or equal to 35, 35-45 and less than or equal to 45 years) and stroke type.

They found 19 relevant studies, including three that reported on overlapping data, with a total of 69,793 young adults (33,775 women and 36,018 men).   

Nine studies did not show a statistically significant sex difference among young adults less than or equal to 45 years. Three studies found higher rates of ischemic stroke among men among young adults less than or equal to 30 to 35 years. Four studies showed more women with ischemic strokes among young adults less than or equal to 35 years.

Overall, there was an effect of a significantly higher incidence of ischemic stroke in women younger than age 35 years, with an incidence rate ratio (IRR) of 1.44. In the 35- to 45-year age group, there was a nonsignificant sex difference in the rate of ischemic stroke, with a slight trend toward a higher incidence in women (IRR, 1.08).

“In this study the sex difference was not clear in the 35-45 age group. But in the age group of over 45 years we know that men have a higher risk of stroke than women, which is probably related to a higher level of atherosclerotic risk factors,” Dr. Poisson commented.

“Interpreting data on stroke in young people is challenging, as stroke is not so common in this population,” she said. “Combining multiple studies helps, but this also introduces a lot of variability, so we need to interpret these results with some caution. However, this is certainly intriguing data and suggests that something interesting may be going on in young adults,” she added. “These observations give us an initial clue that we need to look further into this issue.”

The study did not look at the possible mechanisms behind the results, as the current data came from administrative datasets that are limited in terms of the information collected.  

But Dr. Poisson noted that the traditional risk factors for stroke are high blood pressure and the usual atherosclerotic factors such as high cholesterol.

“These are normally more common in men than in women, and myocardial infarction is more common in younger men than in younger women. But the observation that young women may have a higher risk of stroke than young men suggests that something different may be going on in the mechanism for stroke.” 

She pointed out that women have some unique risk factors for stroke, including oral contraceptive use, pregnancy, and the postpartum period, particularly pre-eclampsia during pregnancy. In addition, migraine, especially migraine with aura, is associated with an increased stroke risk, and migraine is more common in young women than in young men.  

“We don’t completely understand the role of these risk factors, but they may contribute to the results that we found,” Dr. Poisson commented. “The role of estrogen in stroke is complicated. While estrogen is generally thought to be protective against atherosclerotic risk factors, it also increases risk of clotting, so high estrogen states like pregnancy increase risk of stroke,” she added.  

To better understand what is happening, prospectively collected clinical data on younger patients who have had a stroke are needed. Some such studies are underway, but a concerted effort to do this in a large, multicenter registry would be desirable, Dr. Poisson said.

She noted that the presentation of a stroke in young people would be similar to that in the older population, with the most recent acronym to help recognize stroke symptoms being “BE FAST” – balance, eyes (vision), face (drooping), arm, speech (slurred), time (call emergency services quickly).

Call for more women in clinical trials

In an accompanying commentary, Cheryl Bushnell, MD, professor of neurology at Wake Forest School of Medicine, Winston-Salem, N.C., and Moira Kapral, MD, professor in medicine and health policy at the University of Toronto, say these findings support the need for further study to understand and address the causes and risk factors of stroke in young women.

However, they point out that representation and reporting of women in clinical trials of acute stroke continues to be suboptimal, and they call for improved incorporation of sex and gender into study design, analysis, and interpretation, which they say is critical for producing research that is broadly generalizable and applicable to different populations. 

Coauthor Stacey L. Daugherty, MD, is funded by the National Institutes of Health. Dr. Poisson and Dr. Kapral have disclosed no relevant financial relationships. Dr. Bushnell reports ownership interest in Care Directions.

A version of this article first appeared on Medscape.com.

Young women appear to be at a higher risk of ischemic stroke than young men, according to a new systematic review of studies on this topic.

The review included 19 studies that reported on sex-specific stroke incidence among young adults and found that overall, in young adults aged 18-35 years, there were 44% more women with ischemic strokes than men.

This gap narrowed in the age group 35-45 years, for which there was conflicting evidence whether more men or women have ischemic strokes.

“An assertion that young women may be disproportionately at risk of ischemic stroke represents a significant departure from our current scientific understanding and may have important implications about the etiology of ischemic strokes in young adults,” the authors note.

“One of the take-home messages from this study is that stroke happens across the entire age spectrum, including young adults, even if they do not have traditional risk factors,” study coauthor Sharon N. Poisson, MD, associate professor of neurology at the University of Colorado Anschutz Medical Campus, Denver, told this news organization.

“If a young person presents with focal neurological symptoms, the possibility of a stroke should not be discounted just because they may not fit the typical profile of a stroke patient. We need more education of the population that young people – including young women – can have a stroke and that fast action to call emergency services is critical,” she said.  

The study was published online Jan. 24 in the journal Stroke as part of a special “Go Red for Women” spotlight issue.

The researchers note that historically it has been believed that men have a higher incidence of stroke in every age group until very old age. However, recent evidence focused on the young adult age group has reported that there are more young women (ages 18-45) with ischemic strokes compared with young men, suggesting that young women may be disproportionately at risk compared with their male counterparts.

Pointing out that a better understanding of these sex differences is important in implementing strategies that can more effectively prevent and treat strokes in this age group, the researchers conducted the current review to synthesize the updated evidence.

They searched PubMed from January 2008 to July 2021 for relevant studies that were population-based and reported stroke incidence by sex or sex-specific incidence rate ratios of young adults age 45 and younger. Statistical synthesis was performed to estimate sex difference by age group (less than or equal to 35, 35-45 and less than or equal to 45 years) and stroke type.

They found 19 relevant studies, including three that reported on overlapping data, with a total of 69,793 young adults (33,775 women and 36,018 men).   

Nine studies did not show a statistically significant sex difference among young adults less than or equal to 45 years. Three studies found higher rates of ischemic stroke among men among young adults less than or equal to 30 to 35 years. Four studies showed more women with ischemic strokes among young adults less than or equal to 35 years.

Overall, there was an effect of a significantly higher incidence of ischemic stroke in women younger than age 35 years, with an incidence rate ratio (IRR) of 1.44. In the 35- to 45-year age group, there was a nonsignificant sex difference in the rate of ischemic stroke, with a slight trend toward a higher incidence in women (IRR, 1.08).

“In this study the sex difference was not clear in the 35-45 age group. But in the age group of over 45 years we know that men have a higher risk of stroke than women, which is probably related to a higher level of atherosclerotic risk factors,” Dr. Poisson commented.

“Interpreting data on stroke in young people is challenging, as stroke is not so common in this population,” she said. “Combining multiple studies helps, but this also introduces a lot of variability, so we need to interpret these results with some caution. However, this is certainly intriguing data and suggests that something interesting may be going on in young adults,” she added. “These observations give us an initial clue that we need to look further into this issue.”

The study did not look at the possible mechanisms behind the results, as the current data came from administrative datasets that are limited in terms of the information collected.  

But Dr. Poisson noted that the traditional risk factors for stroke are high blood pressure and the usual atherosclerotic factors such as high cholesterol.

“These are normally more common in men than in women, and myocardial infarction is more common in younger men than in younger women. But the observation that young women may have a higher risk of stroke than young men suggests that something different may be going on in the mechanism for stroke.” 

She pointed out that women have some unique risk factors for stroke, including oral contraceptive use, pregnancy, and the postpartum period, particularly pre-eclampsia during pregnancy. In addition, migraine, especially migraine with aura, is associated with an increased stroke risk, and migraine is more common in young women than in young men.  

“We don’t completely understand the role of these risk factors, but they may contribute to the results that we found,” Dr. Poisson commented. “The role of estrogen in stroke is complicated. While estrogen is generally thought to be protective against atherosclerotic risk factors, it also increases risk of clotting, so high estrogen states like pregnancy increase risk of stroke,” she added.  

To better understand what is happening, prospectively collected clinical data on younger patients who have had a stroke are needed. Some such studies are underway, but a concerted effort to do this in a large, multicenter registry would be desirable, Dr. Poisson said.

She noted that the presentation of a stroke in young people would be similar to that in the older population, with the most recent acronym to help recognize stroke symptoms being “BE FAST” – balance, eyes (vision), face (drooping), arm, speech (slurred), time (call emergency services quickly).

Call for more women in clinical trials

In an accompanying commentary, Cheryl Bushnell, MD, professor of neurology at Wake Forest School of Medicine, Winston-Salem, N.C., and Moira Kapral, MD, professor in medicine and health policy at the University of Toronto, say these findings support the need for further study to understand and address the causes and risk factors of stroke in young women.

However, they point out that representation and reporting of women in clinical trials of acute stroke continues to be suboptimal, and they call for improved incorporation of sex and gender into study design, analysis, and interpretation, which they say is critical for producing research that is broadly generalizable and applicable to different populations. 

Coauthor Stacey L. Daugherty, MD, is funded by the National Institutes of Health. Dr. Poisson and Dr. Kapral have disclosed no relevant financial relationships. Dr. Bushnell reports ownership interest in Care Directions.

A version of this article first appeared on Medscape.com.

Patients looking to refill a prescription for apixaban (Eliquis) through CVS Caremark may be in for a surprise following its decision to exclude the direct oral anticoagulant (DOAC) from its formulary starting Jan. 1.

The move leaves just one DOAC, rivaroxaban (Xarelto), on CVS’ commercial formulary and is being assailed as the latest example of “nonmedical switching” used by health insurers to control costs.

In a letter to CVS Caremark backed by 14 provider and patient organizations, the nonprofit Partnership to Advance Cardiovascular Health (PACH) calls on the pharmacy chain to reverse its “dangerously disruptive” decision to force stable patients at high risk of cardiovascular events to switch anticoagulation, without an apparent option to be grandfathered into the new plan.

PACH president Dharmesh Patel, MD, Stern Cardiovascular Center, Memphis, called the formulary change “reckless and irresponsible, especially because the decision is not based in science and evidence, but on budgets. Patients and their health care providers, not insurance companies, need to be trusted to determine what medication is best,” he said in a statement.

Craig Beavers, PharmD, vice president of Baptist Health Paducah, Kentucky, said that, as chair of the American College of Cardiology’s Cardiovascular Team Section, he and other organizations have met with CVS Caremark medical leadership to advocate for patients and to understand the company’s perspective.

“The underlying driver is cost,” he told this news organization.

Current guidelines recommend DOACs in general for a variety of indications, including to reduce the risk of stroke and embolism in nonvalvular atrial fibrillation and to prevent deep vein thrombosis, but there are select instances where a particular DOAC might be more appropriate, he observed.

“Apixaban may be better for a patient with a history of GI bleeding because there’s less GI bleeding, but the guidelines don’t necessarily spell those things out,” Dr. Beavers said. “That’s where the clinician should advocate for their patient and, unfortunately, they are making their decision strictly based off the guidelines.”

Requests to speak with medical officers at CVS Caremark went unanswered, but its executive director of communications, Christina Peaslee, told this news organization that the formulary decision “maintains clinically appropriate, cost-effective prescription coverage” for its clients and members.

“Both the American Heart Association/American College of Cardiology/Heart Rhythm Society and 2021 CHEST guidelines recommend DOACs over warfarin for treatment of various cardiology conditions such as atrial fibrillation, but neither list a specific agent as preferred – showing that consensus clinical guidelines do not favor one over the other,” she said in an email. “Further, Xarelto has more FDA-approved indications than Eliquis (e.g., Xarelto is approved for a reduction in risk of major CV events in patients with CAD or PAD) in addition to all the same FDA indications as Eliquis.”

Ms. Peaslee pointed out that all formulary changes are evaluated by an external medical expert specializing in the disease state, followed by review and approval by an independent national Pharmacy & Therapeutics Committee.

The decision to exclude apixaban is also limited to a “subset of commercial drug lists,” she said, although specifics on which plans and the number of affected patients were not forthcoming.

The choice of DOAC is a timely question in cardiology, with recent studies suggesting an advantage for apixaban over rivaroxaban in reducing the risk of recurrent venous thromboembolism, as well as reducing the risk of major ischemic or hemorrhagic events in atrial fibrillation.

Ms. Peaslee said CVS Caremark closely monitors medical literature for relevant clinical trial data and that most clients allow reasonable formulary exceptions when justified. “This formulary exceptions process has been successfully used for changes of this type and allows patients to get a medication that is safe and effective, as determined by their prescriber.”

The company will also continue to provide “robust, personalized outreach to the small number of members who will need to switch to an alternative medication,” she added.

Dr. Beavers said negotiations with CVS are still in the early stages, but, in the meantime, the ACC is providing health care providers with tools, such as drug copay cards and electronic prior authorizations, to help ensure patients don’t have gaps in coverage.

In a Jan. 14 news release addressing the formulary change, ACC notes that a patient’s pharmacy can also request a one-time override when trying to fill a nonpreferred DOAC in January to buy time if switching medications with their clinician or requesting a formulary exception.

During discussions with CVS Caremark, it says the ACC and the American Society of Hematology “underscored the negative impacts of this decision on patients currently taking one of the nonpreferred DOACs and on those who have previously tried rivaroxaban and changed medications.”

The groups also highlighted difficulties with other prior authorization programs in terms of the need for dedicated staff and time away from direct patient care.

“The ACC and ASH will continue discussions with CVS Caremark regarding the burden on clinicians and the effect of the formulary decision on patient access,” the release says.

In its letter to CVS, PACH argues that the apixaban exclusion will disproportionately affect historically disadvantaged patients, leaving those who can least afford the change with limited options. Notably, no generic is available for either apixaban or rivaroxaban.

The group also highlights a 2019 national poll, in which nearly 40% of patients who had their medication switched were so frustrated that they stopped their medication altogether.

PACH has an online petition against nonmedical switching, which at press time had garnered 2,126 signatures.

One signee, Jan Griffin, who survived bilateral pulmonary embolisms, writes that she has been on Eliquis [apixaban] successfully since her hospital discharge. “Now, as of midnight, Caremark apparently knows better than my hematologist as to what blood thinner is better for me and will no longer cover my Eliquis prescription. This is criminal, immoral, and unethical. #StopTheSwitch.”

A version of this article first appeared on Medscape.com.

Patients looking to refill a prescription for apixaban (Eliquis) through CVS Caremark may be in for a surprise following its decision to exclude the direct oral anticoagulant (DOAC) from its formulary starting Jan. 1.

The move leaves just one DOAC, rivaroxaban (Xarelto), on CVS’ commercial formulary and is being assailed as the latest example of “nonmedical switching” used by health insurers to control costs.

In a letter to CVS Caremark backed by 14 provider and patient organizations, the nonprofit Partnership to Advance Cardiovascular Health (PACH) calls on the pharmacy chain to reverse its “dangerously disruptive” decision to force stable patients at high risk of cardiovascular events to switch anticoagulation, without an apparent option to be grandfathered into the new plan.

PACH president Dharmesh Patel, MD, Stern Cardiovascular Center, Memphis, called the formulary change “reckless and irresponsible, especially because the decision is not based in science and evidence, but on budgets. Patients and their health care providers, not insurance companies, need to be trusted to determine what medication is best,” he said in a statement.

Craig Beavers, PharmD, vice president of Baptist Health Paducah, Kentucky, said that, as chair of the American College of Cardiology’s Cardiovascular Team Section, he and other organizations have met with CVS Caremark medical leadership to advocate for patients and to understand the company’s perspective.

“The underlying driver is cost,” he told this news organization.

Current guidelines recommend DOACs in general for a variety of indications, including to reduce the risk of stroke and embolism in nonvalvular atrial fibrillation and to prevent deep vein thrombosis, but there are select instances where a particular DOAC might be more appropriate, he observed.

“Apixaban may be better for a patient with a history of GI bleeding because there’s less GI bleeding, but the guidelines don’t necessarily spell those things out,” Dr. Beavers said. “That’s where the clinician should advocate for their patient and, unfortunately, they are making their decision strictly based off the guidelines.”

Requests to speak with medical officers at CVS Caremark went unanswered, but its executive director of communications, Christina Peaslee, told this news organization that the formulary decision “maintains clinically appropriate, cost-effective prescription coverage” for its clients and members.

“Both the American Heart Association/American College of Cardiology/Heart Rhythm Society and 2021 CHEST guidelines recommend DOACs over warfarin for treatment of various cardiology conditions such as atrial fibrillation, but neither list a specific agent as preferred – showing that consensus clinical guidelines do not favor one over the other,” she said in an email. “Further, Xarelto has more FDA-approved indications than Eliquis (e.g., Xarelto is approved for a reduction in risk of major CV events in patients with CAD or PAD) in addition to all the same FDA indications as Eliquis.”

Ms. Peaslee pointed out that all formulary changes are evaluated by an external medical expert specializing in the disease state, followed by review and approval by an independent national Pharmacy & Therapeutics Committee.

The decision to exclude apixaban is also limited to a “subset of commercial drug lists,” she said, although specifics on which plans and the number of affected patients were not forthcoming.

The choice of DOAC is a timely question in cardiology, with recent studies suggesting an advantage for apixaban over rivaroxaban in reducing the risk of recurrent venous thromboembolism, as well as reducing the risk of major ischemic or hemorrhagic events in atrial fibrillation.

Ms. Peaslee said CVS Caremark closely monitors medical literature for relevant clinical trial data and that most clients allow reasonable formulary exceptions when justified. “This formulary exceptions process has been successfully used for changes of this type and allows patients to get a medication that is safe and effective, as determined by their prescriber.”

The company will also continue to provide “robust, personalized outreach to the small number of members who will need to switch to an alternative medication,” she added.

Dr. Beavers said negotiations with CVS are still in the early stages, but, in the meantime, the ACC is providing health care providers with tools, such as drug copay cards and electronic prior authorizations, to help ensure patients don’t have gaps in coverage.

In a Jan. 14 news release addressing the formulary change, ACC notes that a patient’s pharmacy can also request a one-time override when trying to fill a nonpreferred DOAC in January to buy time if switching medications with their clinician or requesting a formulary exception.

During discussions with CVS Caremark, it says the ACC and the American Society of Hematology “underscored the negative impacts of this decision on patients currently taking one of the nonpreferred DOACs and on those who have previously tried rivaroxaban and changed medications.”

The groups also highlighted difficulties with other prior authorization programs in terms of the need for dedicated staff and time away from direct patient care.

“The ACC and ASH will continue discussions with CVS Caremark regarding the burden on clinicians and the effect of the formulary decision on patient access,” the release says.

In its letter to CVS, PACH argues that the apixaban exclusion will disproportionately affect historically disadvantaged patients, leaving those who can least afford the change with limited options. Notably, no generic is available for either apixaban or rivaroxaban.

The group also highlights a 2019 national poll, in which nearly 40% of patients who had their medication switched were so frustrated that they stopped their medication altogether.

PACH has an online petition against nonmedical switching, which at press time had garnered 2,126 signatures.

One signee, Jan Griffin, who survived bilateral pulmonary embolisms, writes that she has been on Eliquis [apixaban] successfully since her hospital discharge. “Now, as of midnight, Caremark apparently knows better than my hematologist as to what blood thinner is better for me and will no longer cover my Eliquis prescription. This is criminal, immoral, and unethical. #StopTheSwitch.”

A version of this article first appeared on Medscape.com.

Patients looking to refill a prescription for apixaban (Eliquis) through CVS Caremark may be in for a surprise following its decision to exclude the direct oral anticoagulant (DOAC) from its formulary starting Jan. 1.

The move leaves just one DOAC, rivaroxaban (Xarelto), on CVS’ commercial formulary and is being assailed as the latest example of “nonmedical switching” used by health insurers to control costs.

In a letter to CVS Caremark backed by 14 provider and patient organizations, the nonprofit Partnership to Advance Cardiovascular Health (PACH) calls on the pharmacy chain to reverse its “dangerously disruptive” decision to force stable patients at high risk of cardiovascular events to switch anticoagulation, without an apparent option to be grandfathered into the new plan.

PACH president Dharmesh Patel, MD, Stern Cardiovascular Center, Memphis, called the formulary change “reckless and irresponsible, especially because the decision is not based in science and evidence, but on budgets. Patients and their health care providers, not insurance companies, need to be trusted to determine what medication is best,” he said in a statement.

Craig Beavers, PharmD, vice president of Baptist Health Paducah, Kentucky, said that, as chair of the American College of Cardiology’s Cardiovascular Team Section, he and other organizations have met with CVS Caremark medical leadership to advocate for patients and to understand the company’s perspective.

“The underlying driver is cost,” he told this news organization.

Current guidelines recommend DOACs in general for a variety of indications, including to reduce the risk of stroke and embolism in nonvalvular atrial fibrillation and to prevent deep vein thrombosis, but there are select instances where a particular DOAC might be more appropriate, he observed.

“Apixaban may be better for a patient with a history of GI bleeding because there’s less GI bleeding, but the guidelines don’t necessarily spell those things out,” Dr. Beavers said. “That’s where the clinician should advocate for their patient and, unfortunately, they are making their decision strictly based off the guidelines.”

Requests to speak with medical officers at CVS Caremark went unanswered, but its executive director of communications, Christina Peaslee, told this news organization that the formulary decision “maintains clinically appropriate, cost-effective prescription coverage” for its clients and members.

“Both the American Heart Association/American College of Cardiology/Heart Rhythm Society and 2021 CHEST guidelines recommend DOACs over warfarin for treatment of various cardiology conditions such as atrial fibrillation, but neither list a specific agent as preferred – showing that consensus clinical guidelines do not favor one over the other,” she said in an email. “Further, Xarelto has more FDA-approved indications than Eliquis (e.g., Xarelto is approved for a reduction in risk of major CV events in patients with CAD or PAD) in addition to all the same FDA indications as Eliquis.”

Ms. Peaslee pointed out that all formulary changes are evaluated by an external medical expert specializing in the disease state, followed by review and approval by an independent national Pharmacy & Therapeutics Committee.

The decision to exclude apixaban is also limited to a “subset of commercial drug lists,” she said, although specifics on which plans and the number of affected patients were not forthcoming.

The choice of DOAC is a timely question in cardiology, with recent studies suggesting an advantage for apixaban over rivaroxaban in reducing the risk of recurrent venous thromboembolism, as well as reducing the risk of major ischemic or hemorrhagic events in atrial fibrillation.

Ms. Peaslee said CVS Caremark closely monitors medical literature for relevant clinical trial data and that most clients allow reasonable formulary exceptions when justified. “This formulary exceptions process has been successfully used for changes of this type and allows patients to get a medication that is safe and effective, as determined by their prescriber.”

The company will also continue to provide “robust, personalized outreach to the small number of members who will need to switch to an alternative medication,” she added.

Dr. Beavers said negotiations with CVS are still in the early stages, but, in the meantime, the ACC is providing health care providers with tools, such as drug copay cards and electronic prior authorizations, to help ensure patients don’t have gaps in coverage.

In a Jan. 14 news release addressing the formulary change, ACC notes that a patient’s pharmacy can also request a one-time override when trying to fill a nonpreferred DOAC in January to buy time if switching medications with their clinician or requesting a formulary exception.

During discussions with CVS Caremark, it says the ACC and the American Society of Hematology “underscored the negative impacts of this decision on patients currently taking one of the nonpreferred DOACs and on those who have previously tried rivaroxaban and changed medications.”

The groups also highlighted difficulties with other prior authorization programs in terms of the need for dedicated staff and time away from direct patient care.

“The ACC and ASH will continue discussions with CVS Caremark regarding the burden on clinicians and the effect of the formulary decision on patient access,” the release says.

In its letter to CVS, PACH argues that the apixaban exclusion will disproportionately affect historically disadvantaged patients, leaving those who can least afford the change with limited options. Notably, no generic is available for either apixaban or rivaroxaban.

The group also highlights a 2019 national poll, in which nearly 40% of patients who had their medication switched were so frustrated that they stopped their medication altogether.

PACH has an online petition against nonmedical switching, which at press time had garnered 2,126 signatures.

One signee, Jan Griffin, who survived bilateral pulmonary embolisms, writes that she has been on Eliquis [apixaban] successfully since her hospital discharge. “Now, as of midnight, Caremark apparently knows better than my hematologist as to what blood thinner is better for me and will no longer cover my Eliquis prescription. This is criminal, immoral, and unethical. #StopTheSwitch.”

A version of this article first appeared on Medscape.com.

In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.

But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.

Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.

Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.

If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.

“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”

The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.

The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.

CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.

The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.

CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.

A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”

In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.

In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.

The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.

In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.

Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.

Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.

“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.

Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.

Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.

Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.

“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.

But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.

Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.

Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.

If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.

“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”

The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.

The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.

CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.

The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.

CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.

A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”

In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.

In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.

The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.

In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.

Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.

Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.

“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.

Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.

Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.

Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.

“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.

But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.

Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.

Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.

If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.

“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”

The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.

The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.

CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.

The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.

CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.

A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”

In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.

In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.

The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.

In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.

Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.

Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.

“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.

Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.

Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.

Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.

“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

It has been well established that device closure has, on average, prevented stroke recurrence in people who’ve had patent foramen ovale–associated stroke, but a meta-analysis has drilled down into clinical trials to advance a potentially practice-changing principle: that, while device closure shows an overall benefit, not all patients derive a benefit and some may actually be harmed by the procedure.

What’s more, the researchers developed a scoring system that helps determine which patients are likely to benefit from device closure.

“What was unknown was how to treat individual patients because the decision to close the patent foramen ovale (PFO) is still preference sensitive because the risk of a recurrent stroke is low, and most of the strokes that recur are not terribly severe,” lead study author David M. Kent, MD, MS, said in an interview.

“On top of this,” he said, “it was still suspected that some of the PFOs, even in trials of well-selected patients, may not be causally related to stroke; the stroke may still have another occult cause, such as paroxysmal atrial fibrillation or aortic arch atheroma.” Dr. Kent is a professor of medicine at Tufts University in Boston and director of the Predictive Analytics and Comparative Effectiveness Center there.

The meta-analysis, conducted by the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium, analyzed data from six randomized clinical trials that compared device closure and medical therapy to medical therapy alone in 3,740 patients who had PFO-associated stroke from 2000 to 2017. It was published in JAMA.

Overall, the rate of recurrent ischemic stroke was less than half that in patients who had device closure, compared with those who were on medical therapy: 0.47% (n = 39 of 1,889) vs. 1.09% (n = 82 of 1,851).

The researchers also applied two tools designed to calculate the probability of recurrent stroke in individual patients: Risk of Paradoxical Embolism (RoPE), an index that assigns a score of 0-10 to stratify cryptogenic stroke patients with PFO by the likelihood that the stroke was associated with their PFO; and the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system, which integrates the RoPE score with physiological and anatomical features – namely, the size of the PFO shunt and the presence of an atrial septal aneurysm.

“We came up with a way to more accurately identify those patients who are likely to get the most benefit from PFO closure based on mathematic modeling that estimates an individual’s probability that the PFO is causally related to the stroke,” Dr. Kent said.
 

Multivariate analysis determines risk

The study used a multivariate classification system that Dr. Kent had been developing to perform subgroup analyses of the clinical trials. It assigned patients to three different risk groups based on the likelihood that the PFO was causally related to their stroke: PASCAL categories of unlikely, possible, and probable.

The PASCAL unlikely group had a risk of stroke recurrence in the first 2 years of 3.4% (95% confidence interval, 1.1%-5.7%) if they were on medical therapy, and 4.1% (95% CI, 1.7%-6.4%) if they had device closure. In the PASCAL possible group, those risks were 3.6% (95% CI, 2.4%-4.9%) and 1.5% (95% CI, 0.7-2.3%), respectively. For the probable group, device closure represents “a near perfect therapy” with a 90% risk reduction, Dr. Kent said. “Moreover,” he said, “adverse events of device closure, such as atrial fibrillation, appear to be concentrated in those patients who fall into the unlikely classification, who appear to get no benefit.”

The ideal patient for device closure is age 60 years or younger and without vascular risk factors such as hypertension, diabetes, a history of smoking, or a prior stroke, but has high-risk PFO features such as a large shunt or atrial septal aneurysm, Dr. Kent said.

“We think these findings should be practice changing now,” Dr. Kent said.

It has been well established that device closure has, on average, prevented stroke recurrence in people who’ve had patent foramen ovale–associated stroke, but a meta-analysis has drilled down into clinical trials to advance a potentially practice-changing principle: that, while device closure shows an overall benefit, not all patients derive a benefit and some may actually be harmed by the procedure.

What’s more, the researchers developed a scoring system that helps determine which patients are likely to benefit from device closure.

“What was unknown was how to treat individual patients because the decision to close the patent foramen ovale (PFO) is still preference sensitive because the risk of a recurrent stroke is low, and most of the strokes that recur are not terribly severe,” lead study author David M. Kent, MD, MS, said in an interview.

“On top of this,” he said, “it was still suspected that some of the PFOs, even in trials of well-selected patients, may not be causally related to stroke; the stroke may still have another occult cause, such as paroxysmal atrial fibrillation or aortic arch atheroma.” Dr. Kent is a professor of medicine at Tufts University in Boston and director of the Predictive Analytics and Comparative Effectiveness Center there.

The meta-analysis, conducted by the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium, analyzed data from six randomized clinical trials that compared device closure and medical therapy to medical therapy alone in 3,740 patients who had PFO-associated stroke from 2000 to 2017. It was published in JAMA.

Overall, the rate of recurrent ischemic stroke was less than half that in patients who had device closure, compared with those who were on medical therapy: 0.47% (n = 39 of 1,889) vs. 1.09% (n = 82 of 1,851).

The researchers also applied two tools designed to calculate the probability of recurrent stroke in individual patients: Risk of Paradoxical Embolism (RoPE), an index that assigns a score of 0-10 to stratify cryptogenic stroke patients with PFO by the likelihood that the stroke was associated with their PFO; and the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system, which integrates the RoPE score with physiological and anatomical features – namely, the size of the PFO shunt and the presence of an atrial septal aneurysm.

“We came up with a way to more accurately identify those patients who are likely to get the most benefit from PFO closure based on mathematic modeling that estimates an individual’s probability that the PFO is causally related to the stroke,” Dr. Kent said.
 

Multivariate analysis determines risk

The study used a multivariate classification system that Dr. Kent had been developing to perform subgroup analyses of the clinical trials. It assigned patients to three different risk groups based on the likelihood that the PFO was causally related to their stroke: PASCAL categories of unlikely, possible, and probable.

The PASCAL unlikely group had a risk of stroke recurrence in the first 2 years of 3.4% (95% confidence interval, 1.1%-5.7%) if they were on medical therapy, and 4.1% (95% CI, 1.7%-6.4%) if they had device closure. In the PASCAL possible group, those risks were 3.6% (95% CI, 2.4%-4.9%) and 1.5% (95% CI, 0.7-2.3%), respectively. For the probable group, device closure represents “a near perfect therapy” with a 90% risk reduction, Dr. Kent said. “Moreover,” he said, “adverse events of device closure, such as atrial fibrillation, appear to be concentrated in those patients who fall into the unlikely classification, who appear to get no benefit.”

The ideal patient for device closure is age 60 years or younger and without vascular risk factors such as hypertension, diabetes, a history of smoking, or a prior stroke, but has high-risk PFO features such as a large shunt or atrial septal aneurysm, Dr. Kent said.

“We think these findings should be practice changing now,” Dr. Kent said.

It has been well established that device closure has, on average, prevented stroke recurrence in people who’ve had patent foramen ovale–associated stroke, but a meta-analysis has drilled down into clinical trials to advance a potentially practice-changing principle: that, while device closure shows an overall benefit, not all patients derive a benefit and some may actually be harmed by the procedure.

What’s more, the researchers developed a scoring system that helps determine which patients are likely to benefit from device closure.

“What was unknown was how to treat individual patients because the decision to close the patent foramen ovale (PFO) is still preference sensitive because the risk of a recurrent stroke is low, and most of the strokes that recur are not terribly severe,” lead study author David M. Kent, MD, MS, said in an interview.

“On top of this,” he said, “it was still suspected that some of the PFOs, even in trials of well-selected patients, may not be causally related to stroke; the stroke may still have another occult cause, such as paroxysmal atrial fibrillation or aortic arch atheroma.” Dr. Kent is a professor of medicine at Tufts University in Boston and director of the Predictive Analytics and Comparative Effectiveness Center there.

The meta-analysis, conducted by the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium, analyzed data from six randomized clinical trials that compared device closure and medical therapy to medical therapy alone in 3,740 patients who had PFO-associated stroke from 2000 to 2017. It was published in JAMA.

Overall, the rate of recurrent ischemic stroke was less than half that in patients who had device closure, compared with those who were on medical therapy: 0.47% (n = 39 of 1,889) vs. 1.09% (n = 82 of 1,851).

The researchers also applied two tools designed to calculate the probability of recurrent stroke in individual patients: Risk of Paradoxical Embolism (RoPE), an index that assigns a score of 0-10 to stratify cryptogenic stroke patients with PFO by the likelihood that the stroke was associated with their PFO; and the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system, which integrates the RoPE score with physiological and anatomical features – namely, the size of the PFO shunt and the presence of an atrial septal aneurysm.

“We came up with a way to more accurately identify those patients who are likely to get the most benefit from PFO closure based on mathematic modeling that estimates an individual’s probability that the PFO is causally related to the stroke,” Dr. Kent said.
 

Multivariate analysis determines risk

The study used a multivariate classification system that Dr. Kent had been developing to perform subgroup analyses of the clinical trials. It assigned patients to three different risk groups based on the likelihood that the PFO was causally related to their stroke: PASCAL categories of unlikely, possible, and probable.

The PASCAL unlikely group had a risk of stroke recurrence in the first 2 years of 3.4% (95% confidence interval, 1.1%-5.7%) if they were on medical therapy, and 4.1% (95% CI, 1.7%-6.4%) if they had device closure. In the PASCAL possible group, those risks were 3.6% (95% CI, 2.4%-4.9%) and 1.5% (95% CI, 0.7-2.3%), respectively. For the probable group, device closure represents “a near perfect therapy” with a 90% risk reduction, Dr. Kent said. “Moreover,” he said, “adverse events of device closure, such as atrial fibrillation, appear to be concentrated in those patients who fall into the unlikely classification, who appear to get no benefit.”

The ideal patient for device closure is age 60 years or younger and without vascular risk factors such as hypertension, diabetes, a history of smoking, or a prior stroke, but has high-risk PFO features such as a large shunt or atrial septal aneurysm, Dr. Kent said.

“We think these findings should be practice changing now,” Dr. Kent said.

A panel of experts that advises the Centers for Disease Control and Prevention on the use of vaccines said the Pfizer and Moderna mRNA COVID-19 vaccines should be the preferred shots for adults in the United States because the Johnson & Johnson shot carries the risk of a rare but potentially fatal side effect that causes blood clots and bleeding in the brain.

In an emergency meeting on December 16, the CDC’s Advisory Committee on Immunization Practices, or ACIP, voted unanimously (15-0) to state a preference for the mRNA vaccines over the Johnson & Johnson shot. The vote came after the panel heard a safety update on cases of thrombosis with thrombocytopenia syndrome, or TTS, a condition that causes large clots that deplete the blood of platelets, resulting in uncontrolled bleeding.

The move brings the United States in line with other wealthy countries. In May, Denmark dropped the Johnson & Johnson shot from its vaccination program because of this risk. Australia and Greece have limited the use of a similar vaccine, made by AstraZeneca, in younger people because of the TTS risk. Both vaccines use the envelope of a different kind of virus, called an adenovirus, to sneak the vaccine instructions into cells. On Dec. 16, health officials said they had determined that TTS was likely due to a class effect, meaning it happens with all adenovirus vector vaccines.

The risk of dying from TTS after a Johnson & Johnson shot is extremely rare. There is an estimated 1 death for every 2 million doses of the vaccine given in the general population. That risk is higher for women ages 30 to 49, rising to about 2 deaths for every 1 million doses given in this age group. There’s no question that the Johnson & Johnson shot has saved many more lives than it has taken, experts said

Still, the committee previously paused the use of the Johnson & Johnson vaccine in April after the first cases of TTS came to light. That pause was lifted just 10 days later, after a new warning was added to the vaccine’s label to raise awareness of the risk.

In updating the safety information on Johnson & Johnson, the panel noted that the warning label had not sufficiently lowered the risk of death from TTS. Doctors seem to be aware of the condition because none of the patients who had developed TTS had been treated with the blood thinner heparin, which can make the syndrome worse. But patients continued to die even after the label was added, the panel noted, because TTS can progress so quickly that doctors simply don’t have time to treat it.

For that reason, and because there are other, safer vaccines available, the panel decided to make what’s called a preferential statement, saying the Pfizer and Moderna mRNA vaccines should be preferred over Johnson & Johnson.

The statement leaves the J&J vaccine on the market and available to patients who are at risk of a severe allergic reaction to the mRNA vaccines. It also means that people can still choose the J&J vaccine if they still want it after being informed about the risks.

About 17 million first doses and 900,000 second doses of the Johnson & Johnson vaccine have been given in the United States. Through the end of August, 54 cases of thrombosis with thrombocytopenia syndrome (TTS) have occurred after the J&J shots in the United States. Nearly half of those were in women ages 30 to 49. There have been nine deaths from TTS after Johnson & Johnson shots.

A version of this article first appeared on WebMD.com.

A panel of experts that advises the Centers for Disease Control and Prevention on the use of vaccines said the Pfizer and Moderna mRNA COVID-19 vaccines should be the preferred shots for adults in the United States because the Johnson & Johnson shot carries the risk of a rare but potentially fatal side effect that causes blood clots and bleeding in the brain.

In an emergency meeting on December 16, the CDC’s Advisory Committee on Immunization Practices, or ACIP, voted unanimously (15-0) to state a preference for the mRNA vaccines over the Johnson & Johnson shot. The vote came after the panel heard a safety update on cases of thrombosis with thrombocytopenia syndrome, or TTS, a condition that causes large clots that deplete the blood of platelets, resulting in uncontrolled bleeding.

The move brings the United States in line with other wealthy countries. In May, Denmark dropped the Johnson & Johnson shot from its vaccination program because of this risk. Australia and Greece have limited the use of a similar vaccine, made by AstraZeneca, in younger people because of the TTS risk. Both vaccines use the envelope of a different kind of virus, called an adenovirus, to sneak the vaccine instructions into cells. On Dec. 16, health officials said they had determined that TTS was likely due to a class effect, meaning it happens with all adenovirus vector vaccines.

The risk of dying from TTS after a Johnson & Johnson shot is extremely rare. There is an estimated 1 death for every 2 million doses of the vaccine given in the general population. That risk is higher for women ages 30 to 49, rising to about 2 deaths for every 1 million doses given in this age group. There’s no question that the Johnson & Johnson shot has saved many more lives than it has taken, experts said

Still, the committee previously paused the use of the Johnson & Johnson vaccine in April after the first cases of TTS came to light. That pause was lifted just 10 days later, after a new warning was added to the vaccine’s label to raise awareness of the risk.

In updating the safety information on Johnson & Johnson, the panel noted that the warning label had not sufficiently lowered the risk of death from TTS. Doctors seem to be aware of the condition because none of the patients who had developed TTS had been treated with the blood thinner heparin, which can make the syndrome worse. But patients continued to die even after the label was added, the panel noted, because TTS can progress so quickly that doctors simply don’t have time to treat it.

For that reason, and because there are other, safer vaccines available, the panel decided to make what’s called a preferential statement, saying the Pfizer and Moderna mRNA vaccines should be preferred over Johnson & Johnson.

The statement leaves the J&J vaccine on the market and available to patients who are at risk of a severe allergic reaction to the mRNA vaccines. It also means that people can still choose the J&J vaccine if they still want it after being informed about the risks.

About 17 million first doses and 900,000 second doses of the Johnson & Johnson vaccine have been given in the United States. Through the end of August, 54 cases of thrombosis with thrombocytopenia syndrome (TTS) have occurred after the J&J shots in the United States. Nearly half of those were in women ages 30 to 49. There have been nine deaths from TTS after Johnson & Johnson shots.

A version of this article first appeared on WebMD.com.

A panel of experts that advises the Centers for Disease Control and Prevention on the use of vaccines said the Pfizer and Moderna mRNA COVID-19 vaccines should be the preferred shots for adults in the United States because the Johnson & Johnson shot carries the risk of a rare but potentially fatal side effect that causes blood clots and bleeding in the brain.

In an emergency meeting on December 16, the CDC’s Advisory Committee on Immunization Practices, or ACIP, voted unanimously (15-0) to state a preference for the mRNA vaccines over the Johnson & Johnson shot. The vote came after the panel heard a safety update on cases of thrombosis with thrombocytopenia syndrome, or TTS, a condition that causes large clots that deplete the blood of platelets, resulting in uncontrolled bleeding.

The move brings the United States in line with other wealthy countries. In May, Denmark dropped the Johnson & Johnson shot from its vaccination program because of this risk. Australia and Greece have limited the use of a similar vaccine, made by AstraZeneca, in younger people because of the TTS risk. Both vaccines use the envelope of a different kind of virus, called an adenovirus, to sneak the vaccine instructions into cells. On Dec. 16, health officials said they had determined that TTS was likely due to a class effect, meaning it happens with all adenovirus vector vaccines.

The risk of dying from TTS after a Johnson & Johnson shot is extremely rare. There is an estimated 1 death for every 2 million doses of the vaccine given in the general population. That risk is higher for women ages 30 to 49, rising to about 2 deaths for every 1 million doses given in this age group. There’s no question that the Johnson & Johnson shot has saved many more lives than it has taken, experts said

Still, the committee previously paused the use of the Johnson & Johnson vaccine in April after the first cases of TTS came to light. That pause was lifted just 10 days later, after a new warning was added to the vaccine’s label to raise awareness of the risk.

In updating the safety information on Johnson & Johnson, the panel noted that the warning label had not sufficiently lowered the risk of death from TTS. Doctors seem to be aware of the condition because none of the patients who had developed TTS had been treated with the blood thinner heparin, which can make the syndrome worse. But patients continued to die even after the label was added, the panel noted, because TTS can progress so quickly that doctors simply don’t have time to treat it.

For that reason, and because there are other, safer vaccines available, the panel decided to make what’s called a preferential statement, saying the Pfizer and Moderna mRNA vaccines should be preferred over Johnson & Johnson.

The statement leaves the J&J vaccine on the market and available to patients who are at risk of a severe allergic reaction to the mRNA vaccines. It also means that people can still choose the J&J vaccine if they still want it after being informed about the risks.

About 17 million first doses and 900,000 second doses of the Johnson & Johnson vaccine have been given in the United States. Through the end of August, 54 cases of thrombosis with thrombocytopenia syndrome (TTS) have occurred after the J&J shots in the United States. Nearly half of those were in women ages 30 to 49. There have been nine deaths from TTS after Johnson & Johnson shots.

A version of this article first appeared on WebMD.com.